Taotlus

UURINGU EETILISE HINDAMISE TAOTLUS EESTI BIOEETIKA JA INIMUURINGUTE NÕUKOGULE 1. Uuringu nimetus (ingliskeelsete taotluse puhul tuleb uuringu nimetus ära tuua ka eesti keeles) Idiopaatilise enneaegse munasarja puudulikkuse, korduvate raseduste katkemiste, loote väärarendite ja perinataalsete surmade geneetilised põhjused. 2. Uuringu põhieesmärk kuni 450 tähemärki (0,25 lk) (ingliskeelsete taotluse puhul tuleb uuringu põhieesmärk ära tuua ka eesti keeles) Uurimistöö eesmärgiks on analüüsida Eesti patsientide valimis enneaegse munasarja puudulikkuse (POI), korduvate raseduse katkemiste (KRK), loote väärarendite ja perinataalsete surmade monogeenseid põhjuseid ning tuvastada nende seisundite võimalikke ühiseid geneetilisi tegureid. 3. Vastutava(d) uurija(d) ning tema (nende) kontaktandmed Eesnimi: Maris Perekonnanimi: Laan Ametikoht: Inimese geneetika professor Organisatsioon: Tartu Ülikool, Bio- ja Siirdemeditsiini Instituut (TÜ BSMI), biomeditsiini osakond, inimese geneetika õppetool Telefon: +372 7375008; 53495258 e-post: [email protected] 4. Uuringu läbiviijad (lisada juurde vajalik arv ridu) TÜ Bio- ja siirdemeditsiini instituut Eesnimi: Anu Perekonnanimi: Valkna Ametikoht: Tartu Üllikool, Meditsiinivaldkond, doktorant (arstiteadused); juh. Prof. Maris Laan ja kaasprof. Kristiina Rull Organisatsioon: TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool Eesnimi: Laura Perekonnanimi: Kasak Ametikoht: inimese geneetika lektor Organisatsioon: TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool Eesnimi: Triin Perekonnanimi: Kikas Ametikoht: inimese geneetika lektor Organisatsioon: TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool Eesnimi: Kristin Perekonnanimi: Tamm Ametikoht: biomeditsiini magistrant, TÜ loodus- ja täppisteaduste valdkond, molekulaar ja rakubioloogia instituut, juh. Anu Valkna ja prof. Maris Laan Organisatsioon: TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool Eesnimi: Avirup Perekonnanimi: Dutta Ametikoht: bioinformaatika teadur Organisatsioon: TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool SA Tartu Ülikooli Kliinikum Eesnimi: Kristiina Perekonnanimi: Rull Ametikoht: vanemarst-õppejõud sünnitusabi ja günekoloogia erialal/sünnitusabi, günekoloogia ja geneetika kaasprofessor Organisatsioon: SA TÜ Kliinikumi naistekliinik/TÜ Kliinilise Meditsiini Instituut (TÜ KMI) / TÜ BSMI, biomeditsiini osakond, inimese geneetika õppetool Eesnimi: Aivar Perekonnanimi: Ehrenberg Ametikoht: arst-õppejõud sünnitusabi ja günekoloogia erialal /TÜ Kliinikumi naistekliiniku direktor Organisatsioon: SA TÜ kliinikumi naistekliinik Eesnimi: Aire Perekonnanimi: Sekavin Ametikoht: arst-õppejõud sünnitusabi ja günekoloogia erialal Organisatsioon: SA TÜ Kliinikumi naistekliinik Eesnimi: Eva-Liina Perekonnanimi: Süüden Ametikoht: arst-õppejõud sünnitusabi ja günekoloogia erialal/arst-õppejõud radioloogiakliinikus Organisatsioon: SA TÜ Kliinikumi naistekliinik/SA TÜ kliinikumi radioloogiakliinik Eesnimi: Ele Perekonnanimi: Hanson Ametikoht: arst-õppejõud sünnitusabi ja günekoloogia erialal/arst-õppejõud radioloogiakliinikus/sünnitusabi ja günekoloogia assistent Organisatsioon: SA TÜ Kliinikumi naistekliinik/SA TÜ kliinikumi radioloogiakliinik/TÜ KMI Eesnimi: Margus Perekonnanimi: Punab Ametikoht: TÜ Kliinikumi radioloogiakliiniku, patoloogiateenistuse, ühendlabori, verekeskuse ja apteegi valdkondade juht/meestearst (androloog-uroloog)/ arst-õppejõud ja direktor androloogia erialal/ androloogia professor Organisatsioon: SA TÜ Kliinikum, Meestekliinik/TÜ KMI Eesnimi: Liis Perekonnanimi: Salumäe Ametikoht: patoloog/patoloogiateenistuse direktor Organisatsioon: SA TÜ Kliinikumi patoloogiateenistus Eesnimi: Tiina Perekonnanimi: Kahre Ametikoht: vanemarst-õppejõud pediaatria erialal/kliinilise molekulaargeneetika lektor Organisatsioon: SA TÜ Kliinikumi Ühendlabori kliinilise geneetika keskus/ TÜ KMI AS Ida-Tallinna Keskhaigla Eesnimi: Ülle Perekonnanimi: Jakovlev Ametikoht: endrokrinoloog/endokrinoloogiakeskuse juhataja Organisatsioon: ITK sisekliinik, endokrinoloogiakeskus Eesnimi: Konstantin Perekonnanimi: Ridnõi Ametikoht: osakonna juhataja Organisatsioon: ITK naistekliinik antenataalse diagnostika osakond Eesnimi: Tiina Perekonnanimi: Loog Ametikoht: viljatusravi arst/viljatusravikeskuse juhataja Organisatsioon: ITK naistekliinik Eesnimi: Külli Perekonnanimi: Erlang Ametikoht: günekoloog/Naistehaigustekeskuse naistenõuandla osakonna juhataja Organisatsioon: ITK naistekliinik Eesnimi: Georgi Perekonnanimi: Džaparidze Ametikoht: patoloog/arst-resident sünnitusabi ja günekoloogia erialal Organisatsioon: ITK patoloogiakeskus Uuringusse kaasatud keskuste kooskõlastuse andnud liikmed Eesnimi: Eero Perekonnanimi: Vasar Ametikoht: inimese füsioloogia professor/TÜ BSMI, juhataja Organisatsioon: Tartu Ülikooli meditsiinivaldkond, bio-ja siirdemeditsiini instituut Eesnimi: Helle Perekonnanimi: Karro Ametikoht: sünnitusabi ja günekoloogia professor/ naistekliiniku juhataja Organisatsioon: SA TÜ Kliinikui naistekliinik/TÜ Kliinilise Meditsiini Instituut Eesnimi: Katrin Perekonnanimi: Kaarna Ametikoht: Kliiniliste uuringute keskuse juhataja Organisatsioon: SA TÜ Kliinikum, kliiniliste uuringute keskus Eesnimi: Tarmo Perekonnanimi: Bakler Ametikoht: AS Ida-Tallinna Keskhaigla juhatuse esimees Organisatsioon: AS Ida-Tallinna Keskhaigla 5. Uuringu finantseerimine Finantseerimise allikad Eesti Teadusagentuuri personaalse uurimistoetuse rühmagran t (PRG1021 ) (2021-2025) Uuringu üldmaksumus (summa) 21 DNA eksoomi sekveneerimine : 6300-8400 Eur. muus osas hinnanguliselt alates 10000 Eur (e.g. personalikulu ; arvuti (d) ; eksperimentaalsed kulud jne.) Uuritavale kompensatsiooni maksmine (jah, ei, põhjendus ja summa) Ei Uuritavate kindlustus (jah, ei, kindlustaja ja poliis) Ei 6. Uuringu läbiviimise aeg (algus ja lõpp kuu ja aasta täpsusega) Uuringu teostamine: aprill 2022 – aprill 2032 Terviku uringu pseudonüümitud andmete säilitamine: 1. aprill 2022 – 1. aprill 2052. Kommentaar: Eesti geenivaramu geenidoonorite isikuandmeid taotleme kodeeritud kujul. Uuringu meeskonnal ei ole nende isikute (ega nende pereliikmete) identifitseerimiseks vajalikke isikukoode, nimesid või muid isikuandmeid. EGV juhtude puhul puudub uurijatel pseudonüümimise võti, sest uuringumeeskond taotleb andmeid juba kodeeritult. Geenidoonorite andmete kasutamise ja säilitamise osas ei ole erinevust perioodidel 2022-2032 ja 2032-2052. Enamik käimasoleva tervikuuringu patsiente kaasatakse Eesti Naistekliinikutes. Tervikuuringu pseudonüümimise koodivõtme hävitamine toimub 2052. Peale koodivõtme kustutamist säilivad andmed anonümiseeritult tähtajatult. Tervikuuringu kestus kuni 2052 a. on määratud ja kooskõlastatud, et oleks võimalik läbi viia kaasatud juhtude reproduktiivse tervise häirete ja sellega seotud üldtervise riskide pikaajalisi jätku- ja täiendavaid uuringud vähemalt kaasatud patsientide reproduktiivse ea lõpuni . Pseudonüümimise koodi säilitamine on vajalik ka tagasiside andmiseks kliinikutes kaasatud patsientidele haigusseoseliste geenivariantide leidude ja sellest tuleneva tervisekäsitluse osas. EGV geenidoonorite puhul laiemaid uuringuid rakenda ei saa, sest kõik andmed jõuavad uurijateni kodeeritud kujul ja saadud geneetilisi leide ei saa ka tagasisidestada. Aga kuna EGV doonorid on osa valimist, siis nende andmete säilitamine sarnaselt kliinikutes kaasatud juhtudega võimaldab suurendada tervikuuringus kogutavat andmestikku ja tugevdada üldisemalt genotüüp-fenotüüp analüüside võimsust. 2052 a. ei hävitata ei andmeid ega andmekandjaid. Andmete edaspidine kasutamine toimub anonümiseeritud kujul. 7. Teave sama uuringu projekti varasema või samaaegse hindamise kohta (sh teistes riikides) Uuring on saand T artu Ülikooli Inimuuringute eetika komiteelt kooskõlastuse : 361/T-25 (21.03.2022) 8. Lühiülevaade siiani samal teemal tehtud uuringutest (kuni 900 tähemärki, 0,5 lk) Idiopaatilise enneaegse munasarja puudulikkuse, korduvate raseduste katkemiste, perinataalsete surmajuhtude ja loote väärarendite geneetika ja molekulaarne etioloogia on tihedalt seotud. Geneetilised faktorid võivad mõjutada sugurakkude küpsemist, kvaliteeti ning reservi, mis omakorda mõjutab rasestumisvõimet, raseduse käiku, embrüo implanteerumist ning loote arengut. Teisalt on teada pleiotroopsed embrüogeneesi ja loote arengut mõjutavad geneetilised vead, mis võivad põhjustada nii raseduse katkemisi, loote väärarendeid kui perinataalset loote hukkumist. 8.1 Enneaegse munasarja puudulikkus ja selle geneetilised põhjused Enneaegset munsarja puudulikkust ( premature ovarian insufficiency , POI) defineeritakse kui hüpergonadotroopset hüpogonadismset sündroomi, mille korral aktiivne munasarja talitlus lakkab enne 40. eluaastat ning mida iseloomustavad menstruatsioonihäired, tõusnud gonadotropiinide tase ja madal östradiooli tase. POI sagedus populatsioonis on umbes 1% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lZOkHe2D","properties":{"formattedCitation":"(1\\uc0\\u8211{}3)","plainCitation":"(1–3)","noteIndex":0},"citationItems":[{"id":112,"uris":["http://zotero.org/users/9406326/items/CZ949NDR"],"itemData":{"id":112,"type":"webpage","language":"en","title":"Guideline on the management of premature ovarian insufficiency","URL":"https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx","author":[{"family":"ESHRE","given":""}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2015"]],"season":"Dets"}}},{"id":76,"uris":["http://zotero.org/users/9406326/items/IQSXD68I"],"itemData":{"id":76,"type":"article-journal","abstract":"Premature ovarian insufficiency (POI) is a major cause of female infertility. It is a heterogeneous disease that affects about 1% of women under 40 years of age. POI may be due to abnormal follicle stock formation, increased follicular atresia, impaired recruitment of dominant follicles, blocked follicular maturation or rapid depletion of the follicular stock. It remains idiopathic in most cases but the existence of familial cases shows that it can have a genetic origin. Next generation sequencing (NGS) strategies have allowed the identification of new genes involved in the etiology of POI. Here, I briefly describe some studies demonstrating that pathogenic variants in ‘DNA repair and meiotic genes’ underlie POI. Some of the examples show the power of the combination of classical genetics and NGS in the discovery of novel ‘POI genes’.","container-title":"Biomedical Journal","DOI":"10.1016/j.bj.2020.03.005","ISSN":"23194170","issue":"2","journalAbbreviation":"Biomedical Journal","language":"en","page":"115-123","source":"DOI.org (Crossref)","title":"Primary ovarian insufficiency, meiosis and DNA repair","volume":"43","author":[{"family":"Veitia","given":"Reiner A."}],"issued":{"date-parts":[["2020",4]]}}},{"id":66,"uris":["http://zotero.org/users/9406326/items/E597RY89"],"itemData":{"id":66,"type":"article-journal","abstract":"Background: The current estimates of the prevalence of primary ovarian insufficiency (POI) are very variable, but are in most studies believed to be around 1%. It is also very likely tat the prevalence of POI differs between countries and over time. We therefore aimed to assess the prevalence of primary ovarian insufficiency in Sweden.\nMethods: All 1,036,918 women born between 1973 and 1993 in Sweden were included. The prevalence of POI was based on data from the Swedish Patient Register through the diagnosis code or through the Prescribed Drug Register. The number of women below 40 years of age diagnosed with the ICD-10 diagnoses E28.3 or E89.4, and women who had been dispensed drugs for treatment of climacteric symptoms were included.\nResults: Out of the 1,036,918 women, 19,253 (1.9%) had POI. The prevalence of spontaneous POI was 1.7% and the prevalence of iatrogenic POI was 0.2%. Most women (98.8%) with POI were identified from the Prescribed Drug Register; only 4.1% were found in the Patient Register, whereas 2.9% were identified in both registers.\nConclusions: The total prevalence of POI was 1.9%, 95% CI: 1.7–2.1, indicating a higher prevalence than often previously reported.","container-title":"BMC Women's Health","DOI":"10.1186/s12905-018-0665-2","ISSN":"1472-6874","issue":"1","journalAbbreviation":"BMC Women's Health","language":"en","page":"175","source":"DOI.org (Crossref)","title":"The prevalence of primary ovarian insufficiency in Sweden; a national register study","volume":"18","author":[{"family":"Lagergren","given":"Katarina"},{"family":"Hammar","given":"Mats"},{"family":"Nedstrand","given":"Elizabeth"},{"family":"Bladh","given":"Marie"},{"family":"Sydsjö","given":"Gunilla"}],"issued":{"date-parts":[["2018",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1–3) . POI teadaolevad põhjused on autoimmuunsed haigused (näiteks Addisoni tõbi, hüpotüroidism, DM), geneetilised põhjused (kromosomaalsed häired, geeni FMR1 5’ regulatoorse regioonis asuv CGG-korduste arvu tõusu ehk premutatsioon, iatrogeensed põhjused (keemia- ja kiiritusravi, kirurgilised protseduurid), välja on pakutud ka erinevaid infektsioone (näiteks HIV, mumps) ja keemilisi ained (näiteks ftalaadid, bisfenool A, pestitsiidid, suitsetamine) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bJuQJgki","properties":{"formattedCitation":"(1,4)","plainCitation":"(1,4)","noteIndex":0},"citationItems":[{"id":112,"uris":["http://zotero.org/users/9406326/items/CZ949NDR"],"itemData":{"id":112,"type":"webpage","language":"en","title":"Guideline on the management of premature ovarian insufficiency","URL":"https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx","author":[{"family":"ESHRE","given":""}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2015"]],"season":"Dets"}}},{"id":115,"uris":["http://zotero.org/users/9406326/items/6P8C9D25"],"itemData":{"id":115,"type":"article-journal","abstract":"Because only 25% of cases of premature ovarian insufficiency (POI) have a known etiology, the aim of this review was to summarize the associations and mechanisms of the impact of the environment on this pathology.","container-title":"Environmental Health","DOI":"10.1186/s12940-017-0242-4","ISSN":"1476-069X","issue":"1","journalAbbreviation":"Environmental Health","page":"37","source":"BioMed Central","title":"Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data","title-short":"Environmental pollutants, a possible etiology for premature ovarian insufficiency","volume":"16","author":[{"family":"Vabre","given":"Pauline"},{"family":"Gatimel","given":"Nicolas"},{"family":"Moreau","given":"Jessika"},{"family":"Gayrard","given":"Véronique"},{"family":"Picard-Hagen","given":"Nicole"},{"family":"Parinaud","given":"Jean"},{"family":"Leandri","given":"Roger D."}],"issued":{"date-parts":[["2017",4,7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1,4) . Olenemata etioloogiast peetakse haiguse patoloogiliseks mehhanismiks primordiaalfolliiklite vähesust juba varajases arengustaadiumis, folliiklite atreesia suurenemist või primordiaalfolliiklite küpsemise ja/või värbamise häiret ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1jDwlSc9","properties":{"formattedCitation":"(5)","plainCitation":"(5)","noteIndex":0},"citationItems":[{"id":64,"uris":["http://zotero.org/users/9406326/items/TD2Z65W3"],"itemData":{"id":64,"type":"article-journal","container-title":"Trends in Endocrinology &amp; Metabolism","DOI":"10.1016/j.tem.2018.07.002","ISSN":"10432760","issue":"11","journalAbbreviation":"Trends in Endocrinology &amp; Metabolism","language":"en","page":"795-807","source":"DOI.org (Crossref)","title":"Molecular Genetics of Premature Ovarian Insufficiency","volume":"29","author":[{"family":"Jiao","given":"Xue"},{"family":"Ke","given":"Hanni"},{"family":"Qin","given":"Yingying"},{"family":"Chen","given":"Zi-Jiang"}],"issued":{"date-parts":[["2018",11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (5) . Teadaolevad põhjused selgitavad umbes 10-30% haigusjuhtudest, 70-90% jääb aga haiguse etioloogia selgusetuks ehk idiopaatiliseks ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XMVwVovX","properties":{"formattedCitation":"(1,6,7)","plainCitation":"(1,6,7)","noteIndex":0},"citationItems":[{"id":112,"uris":["http://zotero.org/users/9406326/items/CZ949NDR"],"itemData":{"id":112,"type":"webpage","language":"en","title":"Guideline on the management of premature ovarian insufficiency","URL":"https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx","author":[{"family":"ESHRE","given":""}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2015"]],"season":"Dets"}}},{"id":65,"uris":["http://zotero.org/users/9406326/items/637WXXT9"],"itemData":{"id":65,"type":"article-journal","container-title":"The Journal of Clinical Endocrinology &amp; Metabolism","DOI":"10.1210/jc.2019-00248","ISSN":"0021-972X, 1945-7197","issue":"8","language":"en","page":"3049-3067","source":"DOI.org (Crossref)","title":"Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease","volume":"104","author":[{"family":"Jolly","given":"Angad"},{"family":"Bayram","given":"Yavuz"},{"family":"Turan","given":"Serap"},{"family":"Aycan","given":"Zehra"},{"family":"Tos","given":"Tulay"},{"family":"Abali","given":"Zehra Yavas"},{"family":"Hacihamdioglu","given":"Bulent"},{"family":"Coban Akdemir","given":"Zeynep Hande"},{"family":"Hijazi","given":"Hadia"},{"family":"Bas","given":"Serpil"},{"family":"Atay","given":"Zeynep"},{"family":"Guran","given":"Tulay"},{"family":"Abali","given":"Saygin"},{"family":"Bas","given":"Firdevs"},{"family":"Darendeliler","given":"Feyza"},{"family":"Colombo","given":"Roberto"},{"family":"Barakat","given":"Tahsin Stefan"},{"family":"Rinne","given":"Tuula"},{"family":"White","given":"Janson J"},{"family":"Yesil","given":"Gozde"},{"family":"Gezdirici","given":"Alper"},{"family":"Gulec","given":"Elif Yilmaz"},{"family":"Karaca","given":"Ender"},{"family":"Pehlivan","given":"Davut"},{"family":"Jhangiani","given":"Shalini N"},{"family":"Muzny","given":"Donna M"},{"family":"Poyrazoglu","given":"Sukran"},{"family":"Bereket","given":"Abdullah"},{"family":"Gibbs","given":"Richard A"},{"family":"Posey","given":"Jennifer E"},{"family":"Lupski","given":"James R"}],"issued":{"date-parts":[["2019",8,1]]}}},{"id":57,"uris":["http://zotero.org/users/9406326/items/AEIQJQYY"],"itemData":{"id":57,"type":"article-journal","abstract":"Context: Primary ovarian insufficiency (POI) affects 1% of women under 40 years of age. POI is idiopathic in more than 70% of cases. Though many candidate genes have been identified in recent years, the prevalence and pathogenicity of abnormalities are still difficult to establish.","container-title":"Journal of the Endocrine Society","DOI":"10.1210/jendso/bvab032","ISSN":"2472-1972","issue":"7","language":"en","page":"bvab032","source":"DOI.org (Crossref)","title":"Next Generation Sequencing Should Be Proposed to Every Woman With “Idiopathic” Primary Ovarian Insufficiency","volume":"5","author":[{"family":"Eskenazi","given":"Sarah"},{"family":"Bachelot","given":"Anne"},{"family":"Hugon-Rodin","given":"Justine"},{"family":"Plu-Bureau","given":"Genevieve"},{"family":"Gompel","given":"Anne"},{"family":"Catteau-Jonard","given":"Sophie"},{"family":"Molina-Gomes","given":"Denise"},{"family":"Dewailly","given":"Didier"},{"family":"Dodé","given":"Catherine"},{"family":"Christin-Maitre","given":"Sophie"},{"family":"Touraine","given":"Philippe"}],"issued":{"date-parts":[["2021",7,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1,6,7) . Geneetilisele etioloogiale viitab haiguse perekondlik esinemine, mida on erinevates allikates kirjeldatud 4-30% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UYPqT8Yx","properties":{"formattedCitation":"(8\\uc0\\u8211{}10)","plainCitation":"(8–10)","noteIndex":0},"citationItems":[{"id":70,"uris":["http://zotero.org/users/9406326/items/B42EL8QU"],"itemData":{"id":70,"type":"article-journal","container-title":"Human Reproduction Update","DOI":"10.1093/humupd/dmv036","ISSN":"1355-4786, 1460-2369","issue":"6","journalAbbreviation":"Hum. Reprod. Update","language":"en","page":"787-808","source":"DOI.org (Crossref)","title":"Genetics of primary ovarian insufficiency: new developments and opportunities","title-short":"Genetics of primary ovarian insufficiency","volume":"21","author":[{"family":"Qin","given":"Yingying"},{"family":"Jiao","given":"Xue"},{"family":"Simpson","given":"Joe Leigh"},{"family":"Chen","given":"Zi-Jiang"}],"issued":{"date-parts":[["2015",11]]}}},{"id":122,"uris":["http://zotero.org/users/9406326/items/JP39Y5FN"],"itemData":{"id":122,"type":"article-journal","abstract":"Background\nPremature ovarian failure (POF) is a complex and heterogeneous disorder that is influenced by multiple genetic components. Numerous candidate gene studies designed to identify POF susceptibility loci have been published, but most positive findings have not been confirmed in follow up studies. We sought to determine if sequence variants previously associated with age at natural menopause (AANM) or early menopause (EM) contribute as well to genetic susceptibility to POF.\n\nMethods\nOur study was performed on 371 unrelated idiopathic women with POF and 800 women controls, all Chinese Han. Thirty six SNPs from previous genome-wide association studies (GWAS) responsible for AANM or EM and 3 additional SNPs in ESR1, and 2 additional SNPs in PTHB1 were tested using the Sequenom MassARRAY iPLEX platform for genotyping.\n\nResults\nThree SNPs - rs2278493 in HK3, rs2234693 in ESR1 and rs12611091 in BRSK1 - showed nominally significant association with POF. Thus, a plausible relationship could exist between ESR1, BRSK1, HK3 and POF.\n\nConclusions\nThis largest association study undertaken to determine correlation between POF and AANM/EM revealed three significant SNPs (rs2278493, rs2234693, and rs12611091). All are associated with not only AAWM and EM but also POF. Insights into shared genetic susceptibility between POF and AANM/EM will provide novel entry points for unraveling genetic mechanism involved in ovarian reserve and oocyte aging processes.","container-title":"Orphanet Journal of Rare Diseases","DOI":"10.1186/1750-1172-7-5","ISSN":"1750-1172","journalAbbreviation":"Orphanet J Rare Dis","note":"PMID: 22248077\nPMCID: PMC3275465","page":"5","source":"PubMed Central","title":"ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure","volume":"7","author":[{"family":"Qin","given":"Yingying"},{"family":"Sun","given":"Mei"},{"family":"You","given":"Li"},{"family":"Wei","given":"Deying"},{"family":"Sun","given":"Jielin"},{"family":"Liang","given":"Xiaoyan"},{"family":"Zhang","given":"Bo"},{"family":"Jiang","given":"Hong"},{"family":"Xu","given":"Jianfeng"},{"family":"Chen","given":"Zi-Jiang"}],"issued":{"date-parts":[["2012",1,17]]}}},{"id":62,"uris":["http://zotero.org/users/9406326/items/WN3NTXLQ"],"itemData":{"id":62,"type":"article-journal","abstract":"Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner’s syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.","container-title":"Frontiers in Endocrinology","DOI":"10.3389/fendo.2021.626924","ISSN":"1664-2392","journalAbbreviation":"Front. Endocrinol.","language":"en","page":"626924","source":"DOI.org (Crossref)","title":"Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI)","volume":"12","author":[{"family":"Ishizuka","given":"Bunpei"}],"issued":{"date-parts":[["2021",2,25]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (8–10) . Praeguse ravijuhise kohaselt on geneetilistest uuringutest näidustatud karüotüübi ning FMR1 premutatsiooni määramine. Üksikute kandidaatgeenide määramine on näidustatud vaid konkreetse kandidaatgeeni mutatsiooni kahtluse korral. Selle peamiseks põhjuseks on üksikute geenide sekveneerimise hind ning fakt, et monogeensed mutatsioonid moodustavad teadaolevalt vaid väikese osa POI põhjustest ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hW8O40bq","properties":{"formattedCitation":"(1,10)","plainCitation":"(1,10)","noteIndex":0},"citationItems":[{"id":112,"uris":["http://zotero.org/users/9406326/items/CZ949NDR"],"itemData":{"id":112,"type":"webpage","language":"en","title":"Guideline on the management of premature ovarian insufficiency","URL":"https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx","author":[{"family":"ESHRE","given":""}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2015"]],"season":"Dets"}}},{"id":62,"uris":["http://zotero.org/users/9406326/items/WN3NTXLQ"],"itemData":{"id":62,"type":"article-journal","abstract":"Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner’s syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.","container-title":"Frontiers in Endocrinology","DOI":"10.3389/fendo.2021.626924","ISSN":"1664-2392","journalAbbreviation":"Front. Endocrinol.","language":"en","page":"626924","source":"DOI.org (Crossref)","title":"Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI)","volume":"12","author":[{"family":"Ishizuka","given":"Bunpei"}],"issued":{"date-parts":[["2021",2,25]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1,10) . Vähene geneetiline uurimine kliinilises praktikas on aga üheks põhjuseks, miks paljud patsiendid jäävad ilma geneetilise diagnoosita ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6N6xpPaz","properties":{"formattedCitation":"(11)","plainCitation":"(11)","noteIndex":0},"citationItems":[{"id":63,"uris":["http://zotero.org/users/9406326/items/3YG5X234"],"itemData":{"id":63,"type":"article-journal","abstract":"Ovarian deficiency, including diminished ovarian reserve and premature ovarian insu ffi ciency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insu ffi ciency often has a genetic basis, with genes a ff ecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26–8% of patients with premature ovarian insu ffi ciency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an indepth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insu ffi ciency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insu ffi ciency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insu ffi ciency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.","container-title":"Maturitas","DOI":"10.1016/j.maturitas.2019.10.011","ISSN":"03785122","journalAbbreviation":"Maturitas","language":"en","page":"78-86","source":"DOI.org (Crossref)","title":"Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility","volume":"131","author":[{"family":"Jaillard","given":"Sylvie"},{"family":"Sreenivasan","given":"Rajini"},{"family":"Beaumont","given":"Marion"},{"family":"Robevska","given":"Gorjana"},{"family":"Dubourg","given":"Christèle"},{"family":"Knarston","given":"Ingrid M."},{"family":"Akloul","given":"Linda"},{"family":"Bergen","given":"Jocelyn","non-dropping-particle":"van den"},{"family":"Odent","given":"Sylvie"},{"family":"Croft","given":"Brittany"},{"family":"Jouve","given":"Guilhem"},{"family":"Grover","given":"Sonia R."},{"family":"Duros","given":"Solène"},{"family":"Pimentel","given":"Céline"},{"family":"Belaud-Rotureau","given":"Marc-Antoine"},{"family":"Ayers","given":"Katie L."},{"family":"Ravel","given":"Célia"},{"family":"Tucker","given":"Elena J."},{"family":"Sinclair","given":"Andrew H."}],"issued":{"date-parts":[["2020",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (11) . Tänaste teadmiste kohaselt on kinnitatud 20 POI kandidaatgeeni, kuid kirjandusest võib leida üle 50 kandidaatgeeni, mis veel ootavad lõplike kinnituste saamist ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"y5a7dESQ","properties":{"formattedCitation":"(10,12)","plainCitation":"(10,12)","noteIndex":0},"citationItems":[{"id":62,"uris":["http://zotero.org/users/9406326/items/WN3NTXLQ"],"itemData":{"id":62,"type":"article-journal","abstract":"Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner’s syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.","container-title":"Frontiers in Endocrinology","DOI":"10.3389/fendo.2021.626924","ISSN":"1664-2392","journalAbbreviation":"Front. Endocrinol.","language":"en","page":"626924","source":"DOI.org (Crossref)","title":"Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI)","volume":"12","author":[{"family":"Ishizuka","given":"Bunpei"}],"issued":{"date-parts":[["2021",2,25]]}}},{"id":197,"uris":["http://zotero.org/users/9406326/items/C45WAP8B"],"itemData":{"id":197,"type":"webpage","title":"OMIM - Online Mendelian Inheritance in Man","URL":"https://www.omim.org/","accessed":{"date-parts":[["2021",11,29]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (10,12) . Monogeensete põhjuste uurimisel on oluline teada, mis funktsiooni geen arengus täidab, sest erinevad geenid on ekspresseeritud erinevates arenguetappides ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4SOMrIzL","properties":{"formattedCitation":"(13)","plainCitation":"(13)","noteIndex":0},"citationItems":[{"id":61,"uris":["http://zotero.org/users/9406326/items/3W7BDDHX"],"itemData":{"id":61,"type":"article-journal","container-title":"Trends in Endocrinology &amp; Metabolism","DOI":"10.1016/j.tem.2018.03.010","ISSN":"10432760","issue":"6","journalAbbreviation":"Trends in Endocrinology &amp; Metabolism","language":"en","page":"400-419","source":"DOI.org (Crossref)","title":"Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency","volume":"29","author":[{"family":"Huhtaniemi","given":"Ilpo"},{"family":"Hovatta","given":"Outi"},{"family":"La Marca","given":"Antonio"},{"family":"Livera","given":"Gabriel"},{"family":"Monniaux","given":"Danielle"},{"family":"Persani","given":"Luca"},{"family":"Heddar","given":"Abdelkader"},{"family":"Jarzabek","given":"Katarzyna"},{"family":"Laisk-Podar","given":"Triin"},{"family":"Salumets","given":"Andres"},{"family":"Tapanainen","given":"Juha S."},{"family":"Veitia","given":"Reiner A."},{"family":"Visser","given":"Jenny A."},{"family":"Wieacker","given":"Peter"},{"family":"Wolczynski","given":"Slawomir"},{"family":"Misrahi","given":"Micheline"}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (13) . POI geneetiline etioloogia on tugevalt seotud follikulogeneesi ja munasarjade arenguga ( BMP15, GDF9, NR5A1, FIGLA, FSHR jt.), lisaks on leitud aina rohkem, et arengus mängivad suurt rolli meioosi ning DNA paranduse geenid, seda ilmselt just munarakkude arengu iseärasuse tõttu (munarakk jääb oma arengus kuni puberteedini meioosi I profaasi) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GRfMKhkU","properties":{"formattedCitation":"(1,2,14)","plainCitation":"(1,2,14)","noteIndex":0},"citationItems":[{"id":112,"uris":["http://zotero.org/users/9406326/items/CZ949NDR"],"itemData":{"id":112,"type":"webpage","language":"en","title":"Guideline on the management of premature ovarian insufficiency","URL":"https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx","author":[{"family":"ESHRE","given":""}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2015"]],"season":"Dets"}}},{"id":76,"uris":["http://zotero.org/users/9406326/items/IQSXD68I"],"itemData":{"id":76,"type":"article-journal","abstract":"Premature ovarian insufficiency (POI) is a major cause of female infertility. It is a heterogeneous disease that affects about 1% of women under 40 years of age. POI may be due to abnormal follicle stock formation, increased follicular atresia, impaired recruitment of dominant follicles, blocked follicular maturation or rapid depletion of the follicular stock. It remains idiopathic in most cases but the existence of familial cases shows that it can have a genetic origin. Next generation sequencing (NGS) strategies have allowed the identification of new genes involved in the etiology of POI. Here, I briefly describe some studies demonstrating that pathogenic variants in ‘DNA repair and meiotic genes’ underlie POI. Some of the examples show the power of the combination of classical genetics and NGS in the discovery of novel ‘POI genes’.","container-title":"Biomedical Journal","DOI":"10.1016/j.bj.2020.03.005","ISSN":"23194170","issue":"2","journalAbbreviation":"Biomedical Journal","language":"en","page":"115-123","source":"DOI.org (Crossref)","title":"Primary ovarian insufficiency, meiosis and DNA repair","volume":"43","author":[{"family":"Veitia","given":"Reiner A."}],"issued":{"date-parts":[["2020",4]]}}},{"id":59,"uris":["http://zotero.org/users/9406326/items/WCBP675H"],"itemData":{"id":59,"type":"article-journal","abstract":"Abstract\n Primary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development.","container-title":"Journal of the Endocrine Society","DOI":"10.1210/jendso/bvz037","ISSN":"2472-1972","issue":"2","language":"en","page":"bvz037","source":"DOI.org (Crossref)","title":"Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era","volume":"4","author":[{"family":"França","given":"Monica Malheiros"},{"family":"Mendonca","given":"Berenice Bilharinho"}],"issued":{"date-parts":[["2020",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (1,2,14) . Lisaks on leitud rolli geenidel, mis mõjutavad mitokondreid ( LARS2, HARS2, CLPP, AARS2) , raku kinnitumist ja migratsiooni (ANTXR1), apoptoosi ja autofaagigat ( NANOS3 , EIF4ENIF1) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wo4W64aC","properties":{"formattedCitation":"(13\\uc0\\u8211{}16)","plainCitation":"(13–16)","noteIndex":0},"citationItems":[{"id":61,"uris":["http://zotero.org/users/9406326/items/3W7BDDHX"],"itemData":{"id":61,"type":"article-journal","container-title":"Trends in Endocrinology &amp; Metabolism","DOI":"10.1016/j.tem.2018.03.010","ISSN":"10432760","issue":"6","journalAbbreviation":"Trends in Endocrinology &amp; Metabolism","language":"en","page":"400-419","source":"DOI.org (Crossref)","title":"Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency","volume":"29","author":[{"family":"Huhtaniemi","given":"Ilpo"},{"family":"Hovatta","given":"Outi"},{"family":"La Marca","given":"Antonio"},{"family":"Livera","given":"Gabriel"},{"family":"Monniaux","given":"Danielle"},{"family":"Persani","given":"Luca"},{"family":"Heddar","given":"Abdelkader"},{"family":"Jarzabek","given":"Katarzyna"},{"family":"Laisk-Podar","given":"Triin"},{"family":"Salumets","given":"Andres"},{"family":"Tapanainen","given":"Juha S."},{"family":"Veitia","given":"Reiner A."},{"family":"Visser","given":"Jenny A."},{"family":"Wieacker","given":"Peter"},{"family":"Wolczynski","given":"Slawomir"},{"family":"Misrahi","given":"Micheline"}],"issued":{"date-parts":[["2018",6]]}}},{"id":59,"uris":["http://zotero.org/users/9406326/items/WCBP675H"],"itemData":{"id":59,"type":"article-journal","abstract":"Abstract\n Primary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development.","container-title":"Journal of the Endocrine Society","DOI":"10.1210/jendso/bvz037","ISSN":"2472-1972","issue":"2","language":"en","page":"bvz037","source":"DOI.org (Crossref)","title":"Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era","volume":"4","author":[{"family":"França","given":"Monica Malheiros"},{"family":"Mendonca","given":"Berenice Bilharinho"}],"issued":{"date-parts":[["2020",2,1]]}}},{"id":75,"uris":["http://zotero.org/users/9406326/items/HGEQ6TZQ"],"itemData":{"id":75,"type":"article-journal","abstract":"Abstract\n Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼ 1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.","container-title":"Endocrinology","DOI":"10.1210/en.2019-00441","ISSN":"1945-7170","issue":"10","language":"en","page":"2353-2366","source":"DOI.org (Crossref)","title":"Mitochondrial Dysfunction in Primary Ovarian Insufficiency","volume":"160","author":[{"family":"Tiosano","given":"Dov"},{"family":"Mears","given":"Jason A"},{"family":"Buchner","given":"David A"}],"issued":{"date-parts":[["2019",10,1]]}}},{"id":73,"uris":["http://zotero.org/users/9406326/items/LED8QDSM"],"itemData":{"id":73,"type":"article-journal","container-title":"Nature","DOI":"10.1038/s41586-021-03779-7","ISSN":"0028-0836, 1476-4687","issue":"7872","journalAbbreviation":"Nature","language":"en","page":"393-397","source":"DOI.org (Crossref)","title":"Genetic insights into biological mechanisms governing human ovarian ageing","volume":"596","author":[{"family":"Ruth","given":"Katherine S."},{"family":"Day","given":"Felix R."},{"family":"Hussain","given":"Jazib"},{"family":"Martínez-Marchal","given":"Ana"},{"family":"Aiken","given":"Catherine E."},{"family":"Azad","given":"Ajuna"},{"family":"Thompson","given":"Deborah J."},{"family":"Knoblochova","given":"Lucie"},{"family":"Abe","given":"Hironori"},{"family":"Tarry-Adkins","given":"Jane L."},{"family":"Gonzalez","given":"Javier Martin"},{"family":"Fontanillas","given":"Pierre"},{"family":"Claringbould","given":"Annique"},{"family":"Bakker","given":"Olivier B."},{"family":"Sulem","given":"Patrick"},{"family":"Walters","given":"Robin G."},{"family":"Terao","given":"Chikashi"},{"family":"Turon","given":"Sandra"},{"family":"Horikoshi","given":"Momoko"},{"family":"Lin","given":"Kuang"},{"family":"Onland-Moret","given":"N. Charlotte"},{"family":"Sankar","given":"Aditya"},{"family":"Hertz","given":"Emil Peter Thrane"},{"family":"Timshel","given":"Pascal N."},{"family":"Shukla","given":"Vallari"},{"family":"Borup","given":"Rehannah"},{"family":"Olsen","given":"Kristina W."},{"family":"Aguilera","given":"Paula"},{"family":"Ferrer-Roda","given":"Mònica"},{"family":"Huang","given":"Yan"},{"family":"Stankovic","given":"Stasa"},{"family":"Timmers","given":"Paul R. H. J."},{"family":"Ahearn","given":"Thomas U."},{"family":"Alizadeh","given":"Behrooz Z."},{"family":"Naderi","given":"Elnaz"},{"family":"Andrulis","given":"Irene L."},{"family":"Arnold","given":"Alice M."},{"family":"Aronson","given":"Kristan J."},{"family":"Augustinsson","given":"Annelie"},{"family":"Bandinelli","given":"Stefania"},{"family":"Barbieri","given":"Caterina M."},{"family":"Beaumont","given":"Robin N."},{"family":"Becher","given":"Heiko"},{"family":"Beckmann","given":"Matthias W."},{"family":"Benonisdottir","given":"Stefania"},{"family":"Bergmann","given":"Sven"},{"family":"Bochud","given":"Murielle"},{"family":"Boerwinkle","given":"Eric"},{"family":"Bojesen","given":"Stig E."},{"family":"Bolla","given":"Manjeet K."},{"family":"Boomsma","given":"Dorret I."},{"family":"Bowker","given":"Nicholas"},{"family":"Brody","given":"Jennifer A."},{"family":"Broer","given":"Linda"},{"family":"Buring","given":"Julie E."},{"family":"Campbell","given":"Archie"},{"family":"Campbell","given":"Harry"},{"family":"Castelao","given":"Jose E."},{"family":"Catamo","given":"Eulalia"},{"family":"Chanock","given":"Stephen J."},{"family":"Chenevix-Trench","given":"Georgia"},{"family":"Ciullo","given":"Marina"},{"family":"Corre","given":"Tanguy"},{"family":"Couch","given":"Fergus J."},{"family":"Cox","given":"Angela"},{"family":"Crisponi","given":"Laura"},{"family":"Cross","given":"Simon S."},{"family":"Cucca","given":"Francesco"},{"family":"Czene","given":"Kamila"},{"family":"Smith","given":"George Davey"},{"family":"Geus","given":"Eco J. C. 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R."},{"family":"John","given":"Esther M."},{"family":"Joshi","given":"Peter K."},{"family":"Karasik","given":"David"},{"family":"Kardia","given":"Sharon L. R."},{"family":"Kartsonaki","given":"Christiana"},{"family":"Karlsson","given":"Robert"},{"family":"Kitahara","given":"Cari M."},{"family":"Kolcic","given":"Ivana"},{"family":"Kooperberg","given":"Charles"},{"family":"Kraft","given":"Peter"},{"family":"Kurian","given":"Allison W."},{"family":"Kutalik","given":"Zoltan"},{"family":"La Bianca","given":"Martina"},{"family":"LaChance","given":"Genevieve"},{"family":"Langenberg","given":"Claudia"},{"family":"Launer","given":"Lenore J."},{"family":"Laven","given":"Joop S. E."},{"family":"Lawlor","given":"Deborah A."},{"family":"Le Marchand","given":"Loic"},{"family":"Li","given":"Jingmei"},{"family":"Lindblom","given":"Annika"},{"family":"Lindstrom","given":"Sara"},{"family":"Lindstrom","given":"Tricia"},{"family":"Linet","given":"Martha"},{"family":"Liu","given":"YongMei"},{"family":"Liu","given":"Simin"},{"family":"Luan","given":"Jian’an"},{"family":"Mägi","given":"Reedik"},{"family":"Magnusson","given":"Patrik K. E."},{"family":"Mangino","given":"Massimo"},{"family":"Mannermaa","given":"Arto"},{"family":"Marco","given":"Brumat"},{"family":"Marten","given":"Jonathan"},{"family":"Martin","given":"Nicholas G."},{"family":"Mbarek","given":"Hamdi"},{"family":"McKnight","given":"Barbara"},{"family":"Medland","given":"Sarah E."},{"family":"Meisinger","given":"Christa"},{"family":"Meitinger","given":"Thomas"},{"family":"Menni","given":"Cristina"},{"family":"Metspalu","given":"Andres"},{"family":"Milani","given":"Lili"},{"family":"Milne","given":"Roger L."},{"family":"Montgomery","given":"Grant W."},{"family":"Mook-Kanamori","given":"Dennis O."},{"family":"Mulas","given":"Antonella"},{"family":"Mulligan","given":"Anna M."},{"family":"Murray","given":"Alison"},{"family":"Nalls","given":"Mike A."},{"family":"Newman","given":"Anne"},{"family":"Noordam","given":"Raymond"},{"family":"Nutile","given":"Teresa"},{"family":"Nyholt","given":"Dale R."},{"family":"Olshan","given":"Andrew F."},{"family":"Olsson","given":"Håkan"},{"family":"Painter","given":"Jodie N."},{"family":"Patel","given":"Alpa V."},{"family":"Pedersen","given":"Nancy L."},{"family":"Perjakova","given":"Natalia"},{"family":"Peters","given":"Annette"},{"family":"Peters","given":"Ulrike"},{"family":"Pharoah","given":"Paul D. P."},{"family":"Polasek","given":"Ozren"},{"family":"Porcu","given":"Eleonora"},{"family":"Psaty","given":"Bruce M."},{"family":"Rahman","given":"Iffat"},{"family":"Rennert","given":"Gad"},{"family":"Rennert","given":"Hedy S."},{"family":"Ridker","given":"Paul M."},{"family":"Ring","given":"Susan M."},{"family":"Robino","given":"Antonietta"},{"family":"Rose","given":"Lynda M."},{"family":"Rosendaal","given":"Frits R."},{"family":"Rossouw","given":"Jacques"},{"family":"Rudan","given":"Igor"},{"family":"Rueedi","given":"Rico"},{"family":"Ruggiero","given":"Daniela"},{"family":"Sala","given":"Cinzia F."},{"family":"Saloustros","given":"Emmanouil"},{"family":"Sandler","given":"Dale P."},{"family":"Sanna","given":"Serena"},{"family":"Sawyer","given":"Elinor J."},{"family":"Sarnowski","given":"Chloé"},{"family":"Schlessinger","given":"David"},{"family":"Schmidt","given":"Marjanka K."},{"family":"Schoemaker","given":"Minouk J."},{"family":"Schraut","given":"Katharina E."},{"family":"Scott","given":"Christopher"},{"family":"Shekari","given":"Saleh"},{"family":"Shrikhande","given":"Amruta"},{"family":"Smith","given":"Albert V."},{"family":"Smith","given":"Blair H."},{"family":"Smith","given":"Jennifer A."},{"family":"Sorice","given":"Rossella"},{"family":"Southey","given":"Melissa C."},{"family":"Spector","given":"Tim D."},{"family":"Spinelli","given":"John J."},{"family":"Stampfer","given":"Meir"},{"family":"Stöckl","given":"Doris"},{"family":"Meurs","given":"Joyce B. J.","non-dropping-particle":"van"},{"family":"Strauch","given":"Konstantin"},{"family":"Styrkarsdottir","given":"Unnur"},{"family":"Swerdlow","given":"Anthony J."},{"family":"Tanaka","given":"Toshiko"},{"family":"Teras","given":"Lauren R."},{"family":"Teumer","given":"Alexander"},{"family":"Þorsteinsdottir","given":"Unnur"},{"family":"Timpson","given":"Nicholas J."},{"family":"Toniolo","given":"Daniela"},{"family":"Traglia","given":"Michela"},{"family":"Troester","given":"Melissa A."},{"family":"Truong","given":"Thérèse"},{"family":"Tyrrell","given":"Jessica"},{"family":"Uitterlinden","given":"André G."},{"family":"Ulivi","given":"Sheila"},{"family":"Vachon","given":"Celine M."},{"family":"Vitart","given":"Veronique"},{"family":"Völker","given":"Uwe"},{"family":"Vollenweider","given":"Peter"},{"family":"Völzke","given":"Henry"},{"family":"Wang","given":"Qin"},{"family":"Wareham","given":"Nicholas J."},{"family":"Weinberg","given":"Clarice R."},{"family":"Weir","given":"David R."},{"family":"Wilcox","given":"Amber N."},{"family":"Dijk","given":"Ko Willems","non-dropping-particle":"van"},{"family":"Willemsen","given":"Gonneke"},{"family":"Wilson","given":"James F."},{"family":"Wolffenbuttel","given":"Bruce H. R."},{"family":"Wolk","given":"Alicja"},{"family":"Wood","given":"Andrew R."},{"family":"Zhao","given":"Wei"},{"family":"Zygmunt","given":"Marek"},{"literal":"Biobank-based Integrative Omics Study (BIOS) Consortium"},{"literal":"eQTLGen Consortium"},{"literal":"The Biobank Japan Project"},{"literal":"China Kadoorie Biobank Collaborative Group"},{"literal":"kConFab Investigators"},{"literal":"The LifeLines Cohort Study"},{"literal":"The InterAct consortium"},{"literal":"23andMe Research Team"},{"family":"Chen","given":"Zhengming"},{"family":"Li","given":"Liming"},{"family":"Franke","given":"Lude"},{"family":"Burgess","given":"Stephen"},{"family":"Deelen","given":"Patrick"},{"family":"Pers","given":"Tune H."},{"family":"Grøndahl","given":"Marie Louise"},{"family":"Andersen","given":"Claus Yding"},{"family":"Pujol","given":"Anna"},{"family":"Lopez-Contreras","given":"Andres J."},{"family":"Daniel","given":"Jeremy A."},{"family":"Stefansson","given":"Kari"},{"family":"Chang-Claude","given":"Jenny"},{"family":"Schouw","given":"Yvonne T.","non-dropping-particle":"van der"},{"family":"Lunetta","given":"Kathryn L."},{"family":"Chasman","given":"Daniel I."},{"family":"Easton","given":"Douglas F."},{"family":"Visser","given":"Jenny A."},{"family":"Ozanne","given":"Susan E."},{"family":"Namekawa","given":"Satoshi H."},{"family":"Solc","given":"Petr"},{"family":"Murabito","given":"Joanne M."},{"family":"Ong","given":"Ken K."},{"family":"Hoffmann","given":"Eva R."},{"family":"Murray","given":"Anna"},{"family":"Roig","given":"Ignasi"},{"family":"Perry","given":"John R. B."}],"issued":{"date-parts":[["2021",8,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (13–16) . Meeste puhul võiks POI “võrdeliseks” fenotüübiks pidada mitte-obstruktiivset azoospermiat (NOA- nonobstructive azoospermia) , mille korral mehe ejakulaadis puuduvad spermatosoidid. Nii oogeneesi kui spermatogeneesi üheks võtme-etapiks on I meiootiline jagunemine ja seda reguleerivad samad geenid ja molekulaarsed mehhanismid ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"F1mUuacg","properties":{"formattedCitation":"(17)","plainCitation":"(17)","noteIndex":0},"citationItems":[{"id":110,"uris":["http://zotero.org/users/9406326/items/G4HYU6W2"],"itemData":{"id":110,"type":"article-journal","abstract":"Objective: Primary ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) both represent disease states of early, and often complete, failure of gametogenesis. Because oogenesis and spermatogenesis share the same conserved steps in meiosis I, it is possible that inherited defects in meiosis I could lead to shared causes of both POI and NOA. Currently, known genes that contribute to both POI and NOA are limited. In this review article, we provide a systematic review of genetic mutations in which both POI and NOA phenotypes exist. Evidence Review: A PubMed literature review was conducted from January 1, 2000, through October 2020. We included all studies that demonstrated human cases of POI or NOA due to a specific genetic mutation either within the same family or in separate families.\nResults: We identified 33 papers that encompassed 10 genes of interest with mutations implicated in both NOA and POI. The genes were all involved in processes of meiosis I.\nConclusion: Mutations in genes involved in processes of meiosis I may cause both NOA and POI. Identifying these unique phenotypes among shared genotypes leads to biologic plausibility that the key error occurs early in gametogenesis with an etiology shared among both male and female offspring. From a clinical standpoint, this shared relationship may help us better understand and identify individuals at a high risk of gonadal failure within families and suggests that clinicians obtain the history of opposite-sex family members when approaching a new diagnosis of POI or NOA. (Fertil Steril RevÒ 2021;2:204–13. Ó2021 by American Society for Reproductive Medicine.)","container-title":"F&amp;S Reviews","DOI":"10.1016/j.xfnr.2021.04.001","ISSN":"26665719","issue":"3","journalAbbreviation":"F&amp;S Reviews","language":"en","page":"204-213","source":"DOI.org (Crossref)","title":"Shared genetics between nonobstructive azoospermia and primary ovarian insufficiency","volume":"2","author":[{"family":"Verrilli","given":"Lauren"},{"family":"Johnstone","given":"Erica"},{"family":"Allen-Brady","given":"Kristina"},{"family":"Welt","given":"Corrine"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (17) . Umbes 50% teadaolevates monogeensetest põhjustest kattuvad nii POI kui NOA puhul, kusjuures suure osa ühisosast moodustavad meioosi ja DNA parandusgeenid ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gLmsQS30","properties":{"formattedCitation":"(18)","plainCitation":"(18)","noteIndex":0},"citationItems":[{"id":109,"uris":["http://zotero.org/users/9406326/items/GIS4ZEP6"],"itemData":{"id":109,"type":"article-journal","abstract":"It is estimated that one in 100 men have azoospermia, the complete lack of sperm in the ejaculate. Currently, ~ 20% of azoospermia cases remain idiopathic. Non-obstructive azoospermia (NOA) is mostly explained by congenital factors leading to spermatogenic failure, such as chromosome abnormalities. The knowledge of the monogenic causes of NOA is very limited. High genetic heterogeneity due to the complexity of spermatogenesis and testicular function, lack of non-consanguineous familial cases and confirmatory studies challenge the field. The reported monogenic defects cause syndromic NOA phenotypes presenting also additional congenital problems and isolated NOA cases, explained by spermatogenic defects. The established and recently reported NOA genes (n = 38) represent essential guardians of meiosis, transcriptional and endocrine regulators of reproduction. Despite the list being short, 92% of these loci are predicted to functionally interact with each other (STRING analysis: average 5.21 connections/gene, enrichment P &lt; 10–16). Notably, ~ 50% of NOA genes have also been implicated in primary ovarian insu ffi ciency, amenorrhea and female genital anomalies, referring to overlapping mechanisms. Considering the knowledge from respective female phenotypes and animal models, exploring the scenarios of di/oligogenic and de novo mutations represent perspective directions in the genetic research of NOA. Knowing the exact genetic cause in each patient improves the management of infertility and other health risks (e.g., cancer), and facilitates the counseling of family members about their reproductive health. Uncovering the loci and biological processes implicated in NOA will also broaden the understanding of etiologies behind spermatogenic failure and promote the development of novel non-invasive treatments for male infertility.","container-title":"Human Genetics","DOI":"10.1007/s00439-020-02112-y","ISSN":"0340-6717, 1432-1203","issue":"1","journalAbbreviation":"Hum Genet","language":"en","page":"135-154","source":"DOI.org (Crossref)","title":"Monogenic causes of non-obstructive azoospermia: challenges, established knowledge, limitations and perspectives","title-short":"Monogenic causes of non-obstructive azoospermia","volume":"140","author":[{"family":"Kasak","given":"Laura"},{"family":"Laan","given":"Maris"}],"issued":{"date-parts":[["2021",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (18) . 8.2 Korduvate raseduste katkemised ja nende geneetilised põhjused Korduvaks raseduse katkemise (KRK) kriteeriumiks on 2 või rohkemat raseduse katkemist enne 22. gestatsiooninädalat. KRK sagedus populatsioonis on umbes 1-2%, kusjuures varasemad raseduse katkemised anamneesis suurendavad KRK riski. Teadaolevateks põhjusteks on anatoomilised häired (kõige sagedasemini emaka vahesein), verehüübeprobleemid (näiteks antifosfolipiidsündroom, trombofiilia), endokrinoloogilised probleemid (diabeet, hüpotüroidism, polütsüstiliste munasarjade sündroom-PCOS), olulist rolli mängivad ka elustiili faktorid nagu suitsetamine, liigne alkoholi tarbimine, liigne sportimine ja üle/alakaalulisus. Geneetilistest teguritest on hästi tuntud kromosoomianomaaliad, kusjuures naise vanuse kasvdes kasvab ka risk geneetiliste häirete tekkeks ning raseduste katkemiseks ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vwv37jhp","properties":{"formattedCitation":"(19\\uc0\\u8211{}22)","plainCitation":"(19–22)","noteIndex":0},"citationItems":[{"id":221,"uris":["http://zotero.org/users/9406326/items/C5B8SKTT"],"itemData":{"id":221,"type":"article-journal","abstract":"What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature?The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized.A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update.The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes.Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee.The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations – of which 31 were formulated as strong recommendations and 29 as conditional – and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL.Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised.The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL.The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker’s fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker’s fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.","container-title":"Human Reproduction Open","DOI":"10.1093/hropen/hoy004","ISSN":"2399-3529","issue":"2","journalAbbreviation":"Human Reproduction Open","source":"Silverchair","title":"ESHRE guideline: recurrent pregnancy loss","title-short":"ESHRE guideline","URL":"https://doi.org/10.1093/hropen/hoy004","volume":"2018","author":[{"literal":"The ESHRE Guideline Group on RPL"},{"family":"Bender Atik","given":"Ruth"},{"family":"Christiansen","given":"Ole Bjarne"},{"family":"Elson","given":"Janine"},{"family":"Kolte","given":"Astrid Marie"},{"family":"Lewis","given":"Sheena"},{"family":"Middeldorp","given":"Saskia"},{"family":"Nelen","given":"Willianne"},{"family":"Peramo","given":"Braulio"},{"family":"Quenby","given":"Siobhan"},{"family":"Vermeulen","given":"Nathalie"},{"family":"Goddijn","given":"Mariëtte"}],"accessed":{"date-parts":[["2021",11,30]]},"issued":{"date-parts":[["2018",4,1]]}}},{"id":208,"uris":["http://zotero.org/users/9406326/items/7QMTP58F"],"itemData":{"id":208,"type":"article-journal","abstract":"Objective To evaluate the impact of advanced paternal age on maternal and perinatal outcomes in the United States.\nDesign Retrospective, population based cohort study.\nSetting US.\nPopulation 40 529 905 documented live births between 2007 and 2016.\nMain outcome measures Primary perinatal outcomes were gestational age, birth weight, Apgar score at five minutes, admission to a neonatal intensive care unit, need for postpartum antibiotics, and seizures. Primary maternal outcomes were gestational diabetes and pre-eclampsia. Secondary outcome was the number of preventable perinatal events.\nResults Higher paternal age was associated with an increased risk of premature birth, low birth weight, and low Apgar score. After adjustment for maternal age, infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15), independent of gestational age, and 18% higher odds of seizures (1.18, 0.97 to 1.44) compared with infants of fathers aged 25 to 34 years. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births and 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age.\nConclusions Advanced paternal age is associated with negative effects on both mothers and offspring. Given the relatively low prevalence of advanced paternal age in the US, population level impacts are currently modest. Nevertheless, as advanced paternal age has doubled in the US over the past generation, further investigation is warranted of the impact on birth outcomes and public health.","container-title":"BMJ","DOI":"10.1136/bmj.k4372","ISSN":"0959-8138, 1756-1833","journalAbbreviation":"BMJ","language":"en","note":"publisher: British Medical Journal Publishing Group\nsection: Research\nPMID: 30381468","page":"k4372","source":"www.bmj.com","title":"Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study","title-short":"Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States","volume":"363","author":[{"family":"Khandwala","given":"Yash S."},{"family":"Baker","given":"Valerie L."},{"family":"Shaw","given":"Gary M."},{"family":"Stevenson","given":"David K."},{"family":"Lu","given":"Ying"},{"family":"Eisenberg","given":"Michael L."}],"issued":{"date-parts":[["2018",10,31]]}}},{"id":212,"uris":["http://zotero.org/users/9406326/items/SDE5ZK7Y"],"itemData":{"id":212,"type":"article-journal","abstract":"OBJECTIVE: To assess the association between advanced maternal age (AMA) and adverse pregnancy outcomes.\nDESIGN: Secondary analysis of the facility-based, cross-sectional data of the WHO Multicountry Survey on Maternal and Newborn Health.\nSETTINGS: A total of 359 health facilities in 29 countries in Africa, Asia, Latin America, and the Middle East.\nSAMPLE: A total of 308 149 singleton pregnant women admitted to the participating health facilities.\nMETHODS: We estimated the prevalence of pregnant women with advanced age (35 years or older). We calculated adjusted odds ratios of individual severe maternal and perinatal outcomes in these women, compared with women aged 20-34 years, using a multilevel, multivariate logistic regression model, accounting for clustering effects within countries and health facilities. The confounding factors included facility and individual characteristics, as well as country (classified by maternal mortality ratio level).\nMAIN OUTCOME MEASURES: Severe maternal adverse outcomes, including maternal near miss (MNM), maternal death (MD), and severe maternal outcome (SMO), and perinatal outcomes, including preterm birth (&lt;37 weeks of gestation), stillbirths, early neonatal mortality, perinatal mortality, low birthweight (&lt;2500 g), and neonatal intensive care unit (NICU) admission.\nRESULTS: The prevalence of pregnant women with AMA was 12.3% (37 787/308 149). Advanced maternal age significantly increased the risk of maternal adverse outcomes, including MNM, MD, and SMO, as well as the risk of stillbirths and perinatal mortalities.\nCONCLUSIONS: Advanced maternal age predisposes women to adverse pregnancy outcomes. The findings of this study would facilitate antenatal counselling and management of women in this age category.","container-title":"BJOG: an international journal of obstetrics and gynaecology","DOI":"10.1111/1471-0528.12659","ISSN":"1471-0528","journalAbbreviation":"BJOG","language":"eng","note":"PMID: 24641535","page":"49-56","source":"PubMed","title":"Advanced maternal age and pregnancy outcomes: a multicountry assessment","title-short":"Advanced maternal age and pregnancy outcomes","volume":"121 Suppl 1","author":[{"family":"Laopaiboon","given":"M."},{"family":"Lumbiganon","given":"P."},{"family":"Intarut","given":"N."},{"family":"Mori","given":"R."},{"family":"Ganchimeg","given":"T."},{"family":"Vogel","given":"J. P."},{"family":"Souza","given":"J. P."},{"family":"Gülmezoglu","given":"A. M."},{"literal":"WHO Multicountry Survey on Maternal Newborn Health Research Network"}],"issued":{"date-parts":[["2014",3]]}}},{"id":215,"uris":["http://zotero.org/users/9406326/items/XSE8D9KT"],"itemData":{"id":215,"type":"article-journal","abstract":"OBJECTIVE: To examine the association between maternal age and a wide range of adverse pregnancy outcomes after adjustment for confounding factors in obstetric history and maternal characteristics.\nMETHODS: This was a retrospective study in women with singleton pregnancies attending the first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. Data on maternal characteristics, and medical and obstetric history were collected and pregnancy outcomes ascertained. Maternal age was studied, both as a continuous and as a categorical variable. Regression analysis was performed to examine the association between maternal age and adverse pregnancy outcome including pre-eclampsia, gestational hypertension, gestational diabetes mellitus (GDM), preterm delivery, small-for-gestational age (SGA) neonate, large-for-gestational age (LGA) neonate, miscarriage, stillbirth and elective and emergency Cesarean section.\nRESULTS: The study population included 76 158 singleton pregnancies with a live fetus at 11 + 0 to 13 + 6 weeks. After adjusting for potential maternal and pregnancy confounding variables, advanced maternal age (defined as ≥ 40 years) was associated with increased risk of miscarriage (odds ratio (OR), 2.32 (95% CI, 1.83-2.93); P &lt; 0.001), pre-eclampsia (OR, 1.49 (95% CI, 1.22-1.82); P &lt; 0.001), GDM (OR, 1.88 (95% CI, 1.55-2.29); P &lt; 0.001), SGA (OR, 1.46 (95% CI, 1.27-1.69); P &lt; 0.001) and Cesarean section (OR, 1.95 (95% CI, 1.77-2.14); P &lt; 0.001), but not with stillbirth, gestational hypertension, spontaneous preterm delivery or LGA.\nCONCLUSIONS: Maternal age should be combined with other maternal characteristics and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. Advanced maternal age is a risk factor for miscarriage, pre-eclampsia, SGA, GDM and Cesarean section, but not for stillbirth, gestational hypertension, spontaneous preterm delivery or LGA.","container-title":"Ultrasound in Obstetrics &amp; Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology","DOI":"10.1002/uog.12494","ISSN":"1469-0705","issue":"6","journalAbbreviation":"Ultrasound Obstet Gynecol","language":"eng","note":"PMID: 23630102","page":"634-643","source":"PubMed","title":"Maternal age and adverse pregnancy outcome: a cohort study","title-short":"Maternal age and adverse pregnancy outcome","volume":"42","author":[{"family":"Khalil","given":"A."},{"family":"Syngelaki","given":"A."},{"family":"Maiz","given":"N."},{"family":"Zinevich","given":"Y."},{"family":"Nicolaides","given":"K. H."}],"issued":{"date-parts":[["2013",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (19–22) . Sünnitaja keskmine vanus on aastatega vaid tõusnud, see aga suurendab ka vajadust uute teadmiste ja meetodite rakendamist sünnieelsesse diagnostikasse ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"aDpXdyKC","properties":{"formattedCitation":"(23)","plainCitation":"(23)","noteIndex":0},"citationItems":[{"id":224,"uris":["http://zotero.org/users/9406326/items/P2945J3P"],"itemData":{"id":224,"type":"webpage","abstract":"Rahvastik uueneb sündidega. Sündimus on ühiskondlikult tähtis küsimus, kuid taandub alati igaühe väga isiklikule otsusele, mida tuleb austada. Eestis on sündimus kogu taasiseseisvuse ajal olnud taastetasemest tunduvalt väiksem. Rahvastiku loomulikuks taastumiseks on tähtis, et peres oleks üle kahe lapse.","language":"et","title":"Sünnid | Statistikaamet","URL":"https://www.stat.ee/et/avasta-statistikat/valdkonnad/rahvastik/sunnid","accessed":{"date-parts":[["2021",11,30]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (23) . Võrreldes POI-ga on KRK etioloogia üsna hästi teada. Siiski jääb 25-50% KRK juhtudest idiopaatilisteks . Võimalikuks veel vähe uuritud etioloogiaks on peetud munarakkude reservi suuruse ja kvaliteedi häirumist, mis on ka POI patoloogiliseks mehhanismiks. Seega on loogiline järeldus, et POI ja KRK geneetika on tugevalt seotud. Varastes munaraku arengufaasides tekkinud molekulaarsed häired põhjustavad ebakvaliteetse embrüo arengut ja implanteerumist. Need võivad omakorda põhjustada raseduse katkemisi. Kui munarakkude reserv on ühtlaselt ebakvaliteetne toimub protsess mitmeid kordi. Seega võib KRK olla viide hoopiski munarakkude reservi häiretele ning raseduse kakemised võivad olla eelmänguks POI diagnoosile kuniks ebakvaliteetsete munarakkude reserv on täielikult lõppenud. Teadaolevate monogensete põhjuste hulka kuuluvad näiteks vead geenides GDF9 ja BMP15, mis mõjutavad folliikleid ning embrüo kvaliteeti. Follikulaarset arengus oluliste geenide avaldumist mõjutavad mitmed transkriptsioonifaktorid ( FIGLA, NOBOX, SOHLH1 ja SOHLH2 ), mida on seostatud ka POI etioloogiaga ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dOLqleKW","properties":{"formattedCitation":"(24)","plainCitation":"(24)","noteIndex":0},"citationItems":[{"id":200,"uris":["http://zotero.org/users/9406326/items/3JJ5PZWF"],"itemData":{"id":200,"type":"article-journal","abstract":"Purpose Approximately 1–2% of the women faces three or more successive spontaneous miscarriages termed as recurrent miscarriage (RM). Many clinical factors have been attributed so far to be the potential risk factors in RM, including uterine anomalies, antiphospholipid syndrome, endocrinological abnormalities, chromosomal abnormalities, and infections. However, in spite of extensive studies, reviews, and array of causes known to be associated with RM, about 50% cases encountered by treating physicians remains unknown. The aims of this study were to evaluate recent publications and to explore oocyte-specific genetic factors that may have role in incidence of recurrent miscarriages.\nMethod Recent studies have identified common molecular factors contributing both in establishment of ovarian reserve and in early embryonic development. Also, studies have pointed out the relationship between the age-associated depletion of OR and increase in the risk of miscarriages, thus suggestive of an interacting biology. Here, we have gathered literature evidences in establishing connecting links between genetic factors associated with age induced or pathological OR depletion and idiopathic RM, which are the two extreme ends of female reproductive pathology.\nConclusion In light of connecting etiological link between infertility and RM as reviewed in this study, interrogating the oocytespecific genes with suspected roles in reproductive biology, in cases of unexplained RM, may open new possibilities in widening our understanding of RM pathophysiology.","container-title":"Journal of Assisted Reproduction and Genetics","DOI":"10.1007/s10815-018-1305-3","ISSN":"1058-0468, 1573-7330","issue":"12","journalAbbreviation":"J Assist Reprod Genet","language":"en","page":"2121-2128","source":"DOI.org (Crossref)","title":"Connecting links between genetic factors defining ovarian reserve and recurrent miscarriages","volume":"35","author":[{"family":"Dean","given":"Deepika Delsa"},{"family":"Agarwal","given":"Sarita"},{"family":"Tripathi","given":"Poonam"}],"issued":{"date-parts":[["2018",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (24) . 8.3 Loote väärarendite ja perinataalsete surmade geneetilised põhjused Hinnanguliselt 2-5%-l loodetest esineb kerge või tõsine arenguanomaalia. Surnult sündinud lastest 20% juhtudel on surma põhjuseks väärarend ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xIc0k7UO","properties":{"formattedCitation":"(25\\uc0\\u8211{}27)","plainCitation":"(25–27)","noteIndex":0},"citationItems":[{"id":201,"uris":["http://zotero.org/users/9406326/items/W99ZAENS"],"itemData":{"id":201,"type":"article-journal","abstract":"OBJECTIVES: This report presents 2013 period infant mortality statistics from the linked birth/infant death data set (linked file) by maternal and infant characteristics. The linked file differs from the mortality file, which is based entirely on death certificate data.\nMETHODS: Descriptive tabulations of data are presented and interpreted.\nRESULTS: The U.S. infant mortality rate was 5.96 infant deaths per 1,000 live births in 2013, similar to the rate of 5.98 in 2012. The number of infant deaths was 23,446 in 2013, a decline of 208 infant deaths from 2012. From 2012 to 2013, infant mortality rates were stable for most race and Hispanic origin groups; declines were reported for two Hispanic subgroups: Cuban and Puerto Rican. Since 2005, the most recent high, the U.S. infant mortality rate has declined 13% (from 6.86), with declines in both neonatal and postneonatal mortality overall and for most groups. In 2013, infants born at 37–38 weeks of gestation (early term) had mortality rates that were 63% higher than for full-term (39–40 week) infants. For multiple births, the infant mortality rate was 25.84, 5 times the rate of 5.25 for singleton births. In 2013, 36% of infant deaths were due to preterm-related causes of death, and an additional 15% were due to causes grouped into the sudden unexpected infant death category.","container-title":"National Vital Statistics Reports: From the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System","ISSN":"1551-8922","issue":"9","journalAbbreviation":"Natl Vital Stat Rep","language":"eng","note":"PMID: 26270610","page":"1-30","source":"PubMed","title":"Infant Mortality Statistics From the 2013 Period Linked Birth/Infant Death Data Set","volume":"64","author":[{"family":"Matthews","given":"T. J."},{"family":"MacDorman","given":"Marian F."},{"family":"Thoma","given":"Marie E."}],"issued":{"date-parts":[["2015",8,6]]}}},{"id":203,"uris":["http://zotero.org/users/9406326/items/M9XYWLRR"],"itemData":{"id":203,"type":"article-journal","abstract":"OBJECTIVE: To provide current population-based prevalence and prenatal diagnosis rates (PND) for specified major congenital anomalies in England and Wales to enable monitoring of the Fetal Anomaly Screening Programme (FASP).\nDESIGN: Secondary analysis of prospectively collected registry data.\nSETTING: Seven multiple-source, population-based congenital anomaly registers, members of the British Isles Network of Congenital Anomaly Registers (BINOCAR) in 2005 and 2006.\nPOPULATION: 2,883 births with congenital anomalies from a total of 601,545 live and stillbirths.\nMAIN OUTCOME MEASURES: PND and birth prevalence of selected congenital anomaly groups/subtypes (anencephaly, spina-bifida, serious cardiac, diaphragmatic hernia, gastroschisis, exomphalos, bilateral renal agenesis, lethal/severe skeletal dysplasia, cleft lip with or without cleft palate [CL + /- P]).\nRESULTS: Of the selected anomaly groups, the most frequently reported were serious cardiac (14.1 per 10,000 births [95% CI 13.0-15.2]) and CL + /- P (9.7 per 10,000 births [8.9-10.5]); the least frequent were bilateral renal agenesis and lethal/severe skeletal dysplasia (&lt; 1.5 per 10,000 births). The PND varied for different anomalies from 53.1% (95% CI 43.5-65.2) for serious cardiac anomalies to 99.6% (95% CI 97.9-100.0) for anencephaly. Least variation in PND rates was for anencephaly (range 98.9-100%) and gastroschisis (93.5-100%); greatest variation was for serious cardiac (43.5-65.2%) and lethal/severe skeletal dysplasias (50.0-100%).\nCONCLUSIONS: BINOCAR registers can, uniquely, provide contemporary data on PND and birth prevalence rates to enable monitoring of the ultrasound component of FASP at a national and regional level, allowing comparisons between populations to be made, planning of resources facilitated and assistance for parents making informed decisions on whether to enter the screening programme.","container-title":"Journal of Medical Screening","DOI":"10.1258/jms.2011.010139","ISSN":"1475-5793","issue":"1","journalAbbreviation":"J Med Screen","language":"eng","note":"PMID: 21536809","page":"2-7","source":"PubMed","title":"Monitoring the prenatal detection of structural fetal congenital anomalies in England and Wales: register-based study","title-short":"Monitoring the prenatal detection of structural fetal congenital anomalies in England and Wales","volume":"18","author":[{"family":"Boyd","given":"Patricia A."},{"family":"Tonks","given":"Ann M."},{"family":"Rankin","given":"Judith"},{"family":"Rounding","given":"Catherine"},{"family":"Wellesley","given":"Diana"},{"family":"Draper","given":"Elizabeth S."},{"literal":"BINOCAR Working Group"}],"issued":{"date-parts":[["2011"]]}}},{"id":205,"uris":["http://zotero.org/users/9406326/items/H375F5ZC"],"itemData":{"id":205,"type":"article-journal","abstract":"BACKGROUND: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010.\nMETHODS: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes.\nRESULTS: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p &lt; 0.001) and MCA cases were more frequently prenatally diagnosed (p &lt; 0.001). Live born infants with MCA were more often born preterm (p &lt; 0.01) and with birth weight &lt; 2500 grams (p &lt; 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p &lt; 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p &lt; 0.001).\nCONCLUSION: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems.","container-title":"Birth Defects Research. Part A, Clinical and Molecular Teratology","DOI":"10.1002/bdra.23240","ISSN":"1542-0760","issue":"4","journalAbbreviation":"Birth Defects Res A Clin Mol Teratol","language":"eng","note":"PMID: 24723551","page":"270-276","source":"PubMed","title":"Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study","title-short":"Epidemiology of multiple congenital anomalies in Europe","volume":"100","author":[{"family":"Calzolari","given":"Elisa"},{"family":"Barisic","given":"Ingeborg"},{"family":"Loane","given":"Maria"},{"family":"Morris","given":"Joan"},{"family":"Wellesley","given":"Diana"},{"family":"Dolk","given":"Helen"},{"family":"Addor","given":"Marie-Claude"},{"family":"Arriola","given":"Larraitz"},{"family":"Bianchi","given":"Fabrizio"},{"family":"Neville","given":"Amanda J."},{"family":"Budd","given":"Judith L. S."},{"family":"Klungsoyr","given":"Kari"},{"family":"Khoshnood","given":"Babak"},{"family":"McDonnell","given":"Bob"},{"family":"Nelen","given":"Vera"},{"family":"Queisser-Luft","given":"Annette"},{"family":"Rankin","given":"Judith"},{"family":"Rissmann","given":"Anke"},{"family":"Rounding","given":"Catherine"},{"family":"Tucker","given":"David"},{"family":"Verellen-Dumoulin","given":"Christine"},{"family":"Walle","given":"Hermien","non-dropping-particle":"de"},{"family":"Garne","given":"Ester"}],"issued":{"date-parts":[["2014",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (25–27) . Väärarendite ning geneetiliste haiguste, eelkõige kromosoomianomaaliate, tekkerisk suureneb märgatavalt lapsevanemate vanuse tõustes ning kaasnevate krooniliste haiguste sagedasema esinemise tõttu ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SooiicME","properties":{"formattedCitation":"(20\\uc0\\u8211{}22)","plainCitation":"(20–22)","noteIndex":0},"citationItems":[{"id":208,"uris":["http://zotero.org/users/9406326/items/7QMTP58F"],"itemData":{"id":208,"type":"article-journal","abstract":"Objective To evaluate the impact of advanced paternal age on maternal and perinatal outcomes in the United States.\nDesign Retrospective, population based cohort study.\nSetting US.\nPopulation 40 529 905 documented live births between 2007 and 2016.\nMain outcome measures Primary perinatal outcomes were gestational age, birth weight, Apgar score at five minutes, admission to a neonatal intensive care unit, need for postpartum antibiotics, and seizures. Primary maternal outcomes were gestational diabetes and pre-eclampsia. Secondary outcome was the number of preventable perinatal events.\nResults Higher paternal age was associated with an increased risk of premature birth, low birth weight, and low Apgar score. After adjustment for maternal age, infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15), independent of gestational age, and 18% higher odds of seizures (1.18, 0.97 to 1.44) compared with infants of fathers aged 25 to 34 years. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births and 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age.\nConclusions Advanced paternal age is associated with negative effects on both mothers and offspring. Given the relatively low prevalence of advanced paternal age in the US, population level impacts are currently modest. Nevertheless, as advanced paternal age has doubled in the US over the past generation, further investigation is warranted of the impact on birth outcomes and public health.","container-title":"BMJ","DOI":"10.1136/bmj.k4372","ISSN":"0959-8138, 1756-1833","journalAbbreviation":"BMJ","language":"en","note":"publisher: British Medical Journal Publishing Group\nsection: Research\nPMID: 30381468","page":"k4372","source":"www.bmj.com","title":"Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study","title-short":"Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States","volume":"363","author":[{"family":"Khandwala","given":"Yash S."},{"family":"Baker","given":"Valerie L."},{"family":"Shaw","given":"Gary M."},{"family":"Stevenson","given":"David K."},{"family":"Lu","given":"Ying"},{"family":"Eisenberg","given":"Michael L."}],"issued":{"date-parts":[["2018",10,31]]}}},{"id":212,"uris":["http://zotero.org/users/9406326/items/SDE5ZK7Y"],"itemData":{"id":212,"type":"article-journal","abstract":"OBJECTIVE: To assess the association between advanced maternal age (AMA) and adverse pregnancy outcomes.\nDESIGN: Secondary analysis of the facility-based, cross-sectional data of the WHO Multicountry Survey on Maternal and Newborn Health.\nSETTINGS: A total of 359 health facilities in 29 countries in Africa, Asia, Latin America, and the Middle East.\nSAMPLE: A total of 308 149 singleton pregnant women admitted to the participating health facilities.\nMETHODS: We estimated the prevalence of pregnant women with advanced age (35 years or older). We calculated adjusted odds ratios of individual severe maternal and perinatal outcomes in these women, compared with women aged 20-34 years, using a multilevel, multivariate logistic regression model, accounting for clustering effects within countries and health facilities. The confounding factors included facility and individual characteristics, as well as country (classified by maternal mortality ratio level).\nMAIN OUTCOME MEASURES: Severe maternal adverse outcomes, including maternal near miss (MNM), maternal death (MD), and severe maternal outcome (SMO), and perinatal outcomes, including preterm birth (&lt;37 weeks of gestation), stillbirths, early neonatal mortality, perinatal mortality, low birthweight (&lt;2500 g), and neonatal intensive care unit (NICU) admission.\nRESULTS: The prevalence of pregnant women with AMA was 12.3% (37 787/308 149). Advanced maternal age significantly increased the risk of maternal adverse outcomes, including MNM, MD, and SMO, as well as the risk of stillbirths and perinatal mortalities.\nCONCLUSIONS: Advanced maternal age predisposes women to adverse pregnancy outcomes. The findings of this study would facilitate antenatal counselling and management of women in this age category.","container-title":"BJOG: an international journal of obstetrics and gynaecology","DOI":"10.1111/1471-0528.12659","ISSN":"1471-0528","journalAbbreviation":"BJOG","language":"eng","note":"PMID: 24641535","page":"49-56","source":"PubMed","title":"Advanced maternal age and pregnancy outcomes: a multicountry assessment","title-short":"Advanced maternal age and pregnancy outcomes","volume":"121 Suppl 1","author":[{"family":"Laopaiboon","given":"M."},{"family":"Lumbiganon","given":"P."},{"family":"Intarut","given":"N."},{"family":"Mori","given":"R."},{"family":"Ganchimeg","given":"T."},{"family":"Vogel","given":"J. P."},{"family":"Souza","given":"J. P."},{"family":"Gülmezoglu","given":"A. M."},{"literal":"WHO Multicountry Survey on Maternal Newborn Health Research Network"}],"issued":{"date-parts":[["2014",3]]}}},{"id":215,"uris":["http://zotero.org/users/9406326/items/XSE8D9KT"],"itemData":{"id":215,"type":"article-journal","abstract":"OBJECTIVE: To examine the association between maternal age and a wide range of adverse pregnancy outcomes after adjustment for confounding factors in obstetric history and maternal characteristics.\nMETHODS: This was a retrospective study in women with singleton pregnancies attending the first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. Data on maternal characteristics, and medical and obstetric history were collected and pregnancy outcomes ascertained. Maternal age was studied, both as a continuous and as a categorical variable. Regression analysis was performed to examine the association between maternal age and adverse pregnancy outcome including pre-eclampsia, gestational hypertension, gestational diabetes mellitus (GDM), preterm delivery, small-for-gestational age (SGA) neonate, large-for-gestational age (LGA) neonate, miscarriage, stillbirth and elective and emergency Cesarean section.\nRESULTS: The study population included 76 158 singleton pregnancies with a live fetus at 11 + 0 to 13 + 6 weeks. After adjusting for potential maternal and pregnancy confounding variables, advanced maternal age (defined as ≥ 40 years) was associated with increased risk of miscarriage (odds ratio (OR), 2.32 (95% CI, 1.83-2.93); P &lt; 0.001), pre-eclampsia (OR, 1.49 (95% CI, 1.22-1.82); P &lt; 0.001), GDM (OR, 1.88 (95% CI, 1.55-2.29); P &lt; 0.001), SGA (OR, 1.46 (95% CI, 1.27-1.69); P &lt; 0.001) and Cesarean section (OR, 1.95 (95% CI, 1.77-2.14); P &lt; 0.001), but not with stillbirth, gestational hypertension, spontaneous preterm delivery or LGA.\nCONCLUSIONS: Maternal age should be combined with other maternal characteristics and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. Advanced maternal age is a risk factor for miscarriage, pre-eclampsia, SGA, GDM and Cesarean section, but not for stillbirth, gestational hypertension, spontaneous preterm delivery or LGA.","container-title":"Ultrasound in Obstetrics &amp; Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology","DOI":"10.1002/uog.12494","ISSN":"1469-0705","issue":"6","journalAbbreviation":"Ultrasound Obstet Gynecol","language":"eng","note":"PMID: 23630102","page":"634-643","source":"PubMed","title":"Maternal age and adverse pregnancy outcome: a cohort study","title-short":"Maternal age and adverse pregnancy outcome","volume":"42","author":[{"family":"Khalil","given":"A."},{"family":"Syngelaki","given":"A."},{"family":"Maiz","given":"N."},{"family":"Zinevich","given":"Y."},{"family":"Nicolaides","given":"K. H."}],"issued":{"date-parts":[["2013",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (20–22) . Oluliseks teguriks, mis mõjutab lootel avastatud arengurikke prognoosi, on kromosoomianomaalia või monogeenne haigus . Loote väärarendi või patoloogilise kombineeritud sõeltesti korral leitakse kromosoomianomaalia või koopiaarvu anomaalia 10-13% juhtudest ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"MhwYAoB9","properties":{"formattedCitation":"(28)","plainCitation":"(28)","noteIndex":0},"citationItems":[{"id":217,"uris":["http://zotero.org/users/9406326/items/GU5MPY7J"],"itemData":{"id":217,"type":"article-journal","abstract":"Pärilike haiguste sünnieelne diagnostika on Eestis kasutusel 1990. aastast. Diagnostika põhineb otsesel lootematerjali uuringul, materjali kättesaamiseks kasutatakse invasiivseid protseduure: amniotsenteesi, koorionibiopsiat ja kordotsenteesi. Aastatel 1990–2016 on tehtud ühtekokku 22 342 invasiivset sünnieelse diagnostika protseduuri: 21 150 amniotsenteesi, 1139 koorionibiopsiat ja 53 kordotsenteesi. Kromosoomianomaalia on leitud 1026 (4,6%) juhul, neist 74% moodustasid arvuanomaaliad. Kõige sagedasem anomaalia (n = 435) oli trisoomia 21 (Downi sündroom, DS). Geenihaigusi on diagnoositud 35 juhul. Põhiline sünnieelse diagnostika näidustus on praegu positiivne sõeltest, järgmisena ultraheliuuringul leitud looteanomaalia. Loote kromosoomihaiguste (eelkõige DS) sõeluuring käivitus Eestis 1995. aastal vanuseriski tõttu (vanemad kui 35/37 a). Nooremas vanuserühmas (alla 35 a) alustati II trimestri vereseerumi sõeltesti tegemist 1998. aasta sügisel. 2013. aastal oli skriininguga Eestis hõlmatud 98% rasedatest. Kogu perioodil (1995–2016) diagnoositi sünnieelselt 64% kõikidest DSi­juhtudest. Sünnieelse skriiningu tulemusel on Downi sündoomi sünnisagedus Eestis vähenenud.","container-title":"Eesti Arst","DOI":"10.15157/ea.v0i0.14627","ISSN":"2228-1665","language":"en","source":"ojs.utlib.ee","title":"Pärilike haiguste sünnieelne diagnoosimine Eestis aastatel 1990–2016","URL":"https://ojs.utlib.ee/index.php/EA/article/view/14627","author":[{"family":"Sitska","given":"Mari"}],"accessed":{"date-parts":[["2021",11,29]]},"issued":{"date-parts":[["2018",12,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (28) . Kui loote fenotüübi või/ja perekondliku anamneesi põhjal tekib spetsiifilise monogeense haiguse kahtlus, on võimalik kasutada kliinilise eksoomi analüüsi, mis võimaldab tuvastada haigus-seoselisi muutusi kuni 6700 geenis. Kokku leitakse tõenäoliselt põhjuslik geneetiline rike (kromosoomianomaalia või monogeenne haigus) ligikaudu 20%-l sünnieelselt avastatud väärarendite juhtudest ning sel puhul on võimalik pakkuda kohe geneetilist nõustamist ja aidata perel valida nende jaoks sobilikum taktika. Ligi 80% loote väärarendite ja perinataalsete surmade juhtudest jääb idiopaatiliseks ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KPSSMIug","properties":{"formattedCitation":"(29)","plainCitation":"(29)","noteIndex":0},"citationItems":[{"id":226,"uris":["http://zotero.org/users/9406326/items/B4SB2EY6"],"itemData":{"id":226,"type":"article-journal","abstract":"Objective To assess causation and clinical presentation of major birth defects.\nDesign Population based case cohort.\nSetting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah’s population based surveillance system. All records underwent clinical re-review.\nParticipants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).\nMain outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).\nResults Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).\nConclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.","container-title":"BMJ","DOI":"10.1136/bmj.j2249","ISSN":"0959-8138, 1756-1833","journalAbbreviation":"BMJ","language":"en","note":"publisher: British Medical Journal Publishing Group\nsection: Research\nPMID: 28559234","page":"j2249","source":"www.bmj.com","title":"Etiology and clinical presentation of birth defects: population based study","title-short":"Etiology and clinical presentation of birth defects","volume":"357","author":[{"family":"Feldkamp","given":"Marcia L."},{"family":"Carey","given":"John C."},{"family":"Byrne","given":"Janice L. B."},{"family":"Krikov","given":"Sergey"},{"family":"Botto","given":"Lorenzo D."}],"issued":{"date-parts":[["2017",5,30]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (29) . 9. Planeeritava uuringu põhjendus ning uurimisküsimused ja/või hüpoteesid (kuni 1800 tähemärki, 1 lk) POI, KRK, loote väärarendite ja perinataalsete surmade ühiseks jooneks on suur idiopaatiliste juhtude arv. Nende põhjuseks peetakse veel teadmata geneetilisi tegureid. Täna teadaolevad ühised geneetilised põhjused ning molekulaarsed rajad viitavad nende reproduktiiv- ja arenguhäirete etioloogilisele ühisosale, s.h. võimalikele laia fenotüübilise spektriga avalduvatele pleiotroopsetele vigadele kas ema sugurakkude ja/või embrüo genoomis. Varane POI ning KRK võimalike geneetiliste põhjuste selgitamine, loote väärarendite ja perinataalsete surmade molekulaarne diagnoos on oluline pereplaneerimise seisukohalt. Umbes 5% POI patsientidest on raporteerinud spontaanset rasestumist, mis viitab, et haiguse varastes faasides võib patsiendil veel olla säilunud munarakkude reserv. Teades POI konkreetset geneetilist etioloogiat, saab ideaalis hinnata munarakkude reservi võimalikku kvaliteeti, samuti selgitada KRK riske. Saades varase diagnoosi võib patsient alustada teadlikku pereplaneerimist. Hilisema diagnoosi korral ei pruugi selleks enam võimalust olla. Lisaks eelnenule on teada, et vanuse tõustes suureneb oluliselt ka üldine risk väärarendite ja geneetiliste haiguste tekkeks (4-6). Ka meeste ja naiste ühise viljatusgeneetika tundmine on pereplaneerimise seisukohalt oluline. Konkreetse geenimutatsiooni leidmine NOA diagnoosiga esimese astme meessugulastel võimaldab perekonna naisliikmetel varajast ennetavat geneetilist testimist ning pereplaneerimisel selle tulemuste arvestamist. Kõik need faktorid on olulised arvestades, et Eesti rahvastiku juurdekasv on alla taastootmise lävendi. Vaid 14% sünnitajatest on alla 25 a., keskmise sünnitaja vanus kasvab iga aastaga ning on hetkel 31 a. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7lgHYroW","properties":{"formattedCitation":"(23,30)","plainCitation":"(23,30)","noteIndex":0},"citationItems":[{"id":224,"uris":["http://zotero.org/users/9406326/items/P2945J3P"],"itemData":{"id":224,"type":"webpage","abstract":"Rahvastik uueneb sündidega. Sündimus on ühiskondlikult tähtis küsimus, kuid taandub alati igaühe väga isiklikule otsusele, mida tuleb austada. Eestis on sündimus kogu taasiseseisvuse ajal olnud taastetasemest tunduvalt väiksem. Rahvastiku loomulikuks taastumiseks on tähtis, et peres oleks üle kahe lapse.","language":"et","title":"Sünnid | Statistikaamet","URL":"https://www.stat.ee/et/avasta-statistikat/valdkonnad/rahvastik/sunnid","accessed":{"date-parts":[["2021",11,30]]}}},{"id":148,"uris":["http://zotero.org/users/9406326/items/VQXK6BS5"],"itemData":{"id":148,"type":"webpage","title":"Emadus täna ja eile | Statistikaamet","URL":"https://www.stat.ee/et/uudised/2019/05/06/emadus-tana-ja-eile","accessed":{"date-parts":[["2021",11,29]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (23,30) . Pereplaneerimise seisukohast on oluline ka sünnieelsete väärarendite diagnostika, mille oluliseks osaks on ka geneetilise etioloogia kindlaks tegemine. Kui suudaksime sünnieelselt rikke olemust täpselt kirjeldada ning sellest tulenevalt prognoosi hinnata, saaksime valida parima taktika. Näiteks, kui neuraaltoru defekt paikneb kaela või rindkere piirkonnas, on lapse suremus peaaegu 100%. Kui rike paikneb aga nimmepiirkonnas, siis on suremus vaid 10% (9) ja osadel juhtudel on võimalik lootekirurgia abil üsasiseselt neuraaltoru defekti korrigeerida, et lapse sünnijärgse närvikahjustuse riski vähendada. Teades kõikide eelmainitud seisundite ühiseid geneetilisi ja molekulaarseid tagamaid on võimalik täpsemalt hinnata inimese tervist ning rakendada võimalikult individuaalset ennetus-, nõustamis- ja raviplaani. Geneetilise etioloogia teadmine võimaldab hinnata patsiendi võimalikke kaasuvaid terviseriske s.h perekonnas esinevat suurenenud vähiriski. Näiteks on suurenenud vähiriski seostatud BRCA2, FANCM, STAG3 geenide erinevate variantidega, mida on pakutud välja ka POI etioloogiana. Seos kasvajate ning viljatushäirete vahel on üheks põhjuseks, miks geneetiline diagnoos ongi oluline: tänu sellele on patsienti võimalik nõustada ning haigust sagedasema uurimisega varasemates staadiumites avastada ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qEnGlRFt","properties":{"formattedCitation":"(13)","plainCitation":"(13)","noteIndex":0},"citationItems":[{"id":61,"uris":["http://zotero.org/users/9406326/items/3W7BDDHX"],"itemData":{"id":61,"type":"article-journal","container-title":"Trends in Endocrinology &amp; Metabolism","DOI":"10.1016/j.tem.2018.03.010","ISSN":"10432760","issue":"6","journalAbbreviation":"Trends in Endocrinology &amp; Metabolism","language":"en","page":"400-419","source":"DOI.org (Crossref)","title":"Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency","volume":"29","author":[{"family":"Huhtaniemi","given":"Ilpo"},{"family":"Hovatta","given":"Outi"},{"family":"La Marca","given":"Antonio"},{"family":"Livera","given":"Gabriel"},{"family":"Monniaux","given":"Danielle"},{"family":"Persani","given":"Luca"},{"family":"Heddar","given":"Abdelkader"},{"family":"Jarzabek","given":"Katarzyna"},{"family":"Laisk-Podar","given":"Triin"},{"family":"Salumets","given":"Andres"},{"family":"Tapanainen","given":"Juha S."},{"family":"Veitia","given":"Reiner A."},{"family":"Visser","given":"Jenny A."},{"family":"Wieacker","given":"Peter"},{"family":"Wolczynski","given":"Slawomir"},{"family":"Misrahi","given":"Micheline"}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (13) . Ülalnimetatud reproduktiivhäirele kliinilise käsitluse meetmete hulka kuuluvad süptomaatika leevendamine (näiteks POI korral osteoporoosi ja kardivaskulaarsete haiguste riski vähendamiseks ning klimakteeriliste sümptomite korral varane hormoonasendusravi), erinevad pereplaneerimise võtted (IVF, munaraku/sperma doonorlus), konkreetse väärarendi korrigeerimiseks erinevad kirurgilised võtted. Lisaks nõuab reproduktiivhäiretega seotud diagnoosi saamine korrektset ja eetilist nõustamist ning toetust, sest näiteks POI patsientidel on sagedaseks probleemiks depressioon ja ärevus. Konkreetse geenimutatsiooni leidmine võib parandada POI diagnoosiga patsiendi leplikust haigusega ja määratud raviga parandades tema elukvaliteeti ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ij4dapat","properties":{"formattedCitation":"(31,32)","plainCitation":"(31,32)","noteIndex":0},"citationItems":[{"id":165,"uris":["http://zotero.org/users/9406326/items/KJQ9GK4D"],"itemData":{"id":165,"type":"article-journal","abstract":"Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼ 50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women.","container-title":"Fertility and Sterility","DOI":"10.1016/j.fertnstert.2016.09.046","ISSN":"1556-5653","issue":"7","journalAbbreviation":"Fertil Steril","language":"eng","note":"PMID: 27912889\nPMCID: PMC5137796","page":"1588-1599","source":"PubMed","title":"Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause","volume":"106","author":[{"family":"Sullivan","given":"Shannon D."},{"family":"Sarrel","given":"Philip M."},{"family":"Nelson","given":"Lawrence M."}],"issued":{"date-parts":[["2016",12]]}}},{"id":168,"uris":["http://zotero.org/users/9406326/items/A9ICIUJ6"],"itemData":{"id":168,"type":"article-journal","abstract":"Premature ovarian insufficiency leads to through infertility and estrogen deficiency. Optimal management encompasses estrogen replacement therapy. Long-term outcome of women with POI is not known. We design a study to evaluate the medical care, hormone replacement therapy compliance and bone mineral density (BMD) in POI women with at least a five-year follow-up after the first evaluation. One hundred and sixty-two patients (37.3±8.0 years) were evaluated (follow-up 7.9±2.8 years). Sixty-nine patients (42.6%) had stopped their hormone replacement therapy (HRT) for at least one year during the follow up period. BMD determination at initial evaluation and at follow-up visit was completed in 92 patients. At first evaluation, 28 patients (30%) had osteopenia and 7 (8%) had osteoporosis. At follow up, 31 women (34%) had BMD impairment with osteopenia in 61% and osteoporosis in 5%. In univariate analysis and multivariate analysis, there was a significant loss of femoral BMD in women who had stopped their HRT for over a year. In conclusion, this first study concerning long-term follow-up of POI patients shows the poor compliance to their HRT, despite its importance in the prevention of bone demineralization. This study reinforces the need for follow up and specific care for POI women.","container-title":"PLoS ONE","DOI":"10.1371/journal.pone.0164638","ISSN":"1932-6203","issue":"12","journalAbbreviation":"PLoS One","note":"PMID: 27906970\nPMCID: PMC5132216","page":"e0164638","source":"PubMed Central","title":"Poor Compliance to Hormone Therapy and Decreased Bone Mineral Density in Women with Premature Ovarian Insufficiency","volume":"11","author":[{"family":"Bachelot","given":"Anne"},{"family":"Nicolas","given":"Carole"},{"family":"Gricourt","given":"Solenne"},{"family":"Dulon","given":"Jérôme"},{"family":"Leban","given":"Monique"},{"family":"Golmard","given":"Jean Louis"},{"family":"Touraine","given":"Philippe"}],"issued":{"date-parts":[["2016",12,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (31,32) . Samuti võimaldavad uued teadmised molekulaarpatoloogilistest mehhanismidest arendada välja uusi ravivõtteid. Näiteks on munasarja fragmenteerimise abil suudetud mõjutada Hippo signaalrada, mille tulemusena aktiviseeriti in vitro nn. „uinunud“ folliiklid ning inimmudelitel saavutati ka rasedusi ja üks elussünd ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"i3bX7oIv","properties":{"formattedCitation":"(33)","plainCitation":"(33)","noteIndex":0},"citationItems":[{"id":194,"uris":["http://zotero.org/users/9406326/items/IHV8UYM4"],"itemData":{"id":194,"type":"article-journal","abstract":"Human ovaries hold follicles containing oocytes. When follicles mature, they release eggs for fertilization. Patients with primary ovarian insufficiency develop menopausal symptoms at less than 40 y of age. They have few remaining follicles and their only chance for bearing a baby is through egg donation. Kawamura et al. demonstrated that Hippo and Akt signaling pathways regulate follicle growth. Using an in vitro activation approach, they first removed ovaries from infertile patients, followed by fragmentation to disrupt Hippo signaling and drug treatment to stimulate Akt signaling. After grafting ovarian tissues back to patients, they found rapid follicle growth in some patients and successfully retrieved mature eggs. After in vitro fertilization and embryo transfer, a live birth is now reported., Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation–in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.","container-title":"Proceedings of the National Academy of Sciences of the United States of America","DOI":"10.1073/pnas.1312830110","ISSN":"0027-8424","issue":"43","journalAbbreviation":"Proc Natl Acad Sci U S A","note":"PMID: 24082083\nPMCID: PMC3808580","page":"17474-17479","source":"PubMed Central","title":"Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment","volume":"110","author":[{"family":"Kawamura","given":"Kazuhiro"},{"family":"Cheng","given":"Yuan"},{"family":"Suzuki","given":"Nao"},{"family":"Deguchi","given":"Masashi"},{"family":"Sato","given":"Yorino"},{"family":"Takae","given":"Seido"},{"family":"Ho","given":"Chi-hong"},{"family":"Kawamura","given":"Nanami"},{"family":"Tamura","given":"Midori"},{"family":"Hashimoto","given":"Shu"},{"family":"Sugishita","given":"Yodo"},{"family":"Morimoto","given":"Yoshiharu"},{"family":"Hosoi","given":"Yoshihiko"},{"family":"Yoshioka","given":"Nobuhito"},{"family":"Ishizuka","given":"Bunpei"},{"family":"Hsueh","given":"Aaron J."}],"issued":{"date-parts":[["2013",10,22]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (33) . Kirjanduse andmetel võime leida sadu artikleid POI-st, KRK-st ja loote väärarenditest ning perinataalsetest surmadest, mis käsitlevad sündroomide erinevaid aspekte, kuid väheseid, mis keskenduksid nende geneetika ühisosale. Tihti viivad erinevate seisundite uuringuid läbi erinevad uurimisrühmad, mistõttu ühiste faktorite leidmine on keeruline. Täna teadaolevate kandidaatgeenide abil on võimalik anda täpne molekulaarne diagnoos vaid väikesele hulgale patsientidest, enamik aga jääb vaatamata pidevalt uuenevatele teadmistele ilma geneetilise diagnoosita. Tervikuuringu eesmärgiks on analüüsida Eesti valimis idiopaatilise ehk seletamatu enneaegse munasarja puudulikkuse (premature ovarian insufficiency, POI), korduvate raseduse katkemiste (KRK), loote väärarendite ja perinataalsete surmade monogeenseid põhjuseid ning tuvastada nende seisundite võimalikke ühiseid geneetilisi tegureid. EBINile tehtud taotluse eesmärgiks on kaasata Eesti Geenivaramu POI sümptomite ja/või diagnoosiga geenidoonoreid suurendamaks ja võimendamaks Tartu ja Tallinna Naistekliinikutes (SA TÜK, AS ITK) tervikuuringusse kogutavat valimit. Uuringusse soovime kaasata konkreetsetele kriteeriumitele vastavad 21 geenidoonori t , kes on Eesti Geenivaramusse eelnevalt andnud nõusoleku andemete töötlemiseks. EBIN taotlusega seotud uurimisküsimused: • Millised on idiopaatilise POI monogeensed ehk ühest geeniveast tingitud põhjused? • Millised on naiste reproduktiivhäirete ühised ehk pleiotroopsed monogeensed põhjused? • Kuidas saadud teadmisi oleks võimalik rakendada kliinilisse praktikasse? Hüpoteesid: • Idiopaatilise POI juhud on põhjustatud veel teadmata monogeensetest geneetilistest põhjustest • POI, KRK, loote väärarendite ja perinataalsete surmade geneetiline etioloogia on osaliselt kattuv ja selle arvesse võtmine tõhustab patsientide kliinilist käsitlust 10. Uurimismetoodika (kuni 1800 tähemärki, 1 lk) Täiseksoomide sekveneerimise ning andmete genereerimise teenus tellitakse Helsingi Ülikooli FIMM ( Institute for Molecular Medicine Finland, https://www2.helsinki.fi/en/hilife-fimm ) sekveneerimise tuumiklaborist, millega on BSMI inimese geneetika õppetooli pikaajaline koostöö. Teenuslabor on DNA sekveneerimise ja genotüpiseerimise partneriks Helsingi Ülikooli Meilahti Haigla igapäevases kliinilises töös, seega on tagatud nii patsientide DNAde kui sekveneerimise andmete ohutu töötlemise, hoidmise ja transportimise kõrge kvaliteet. Kuna andmed ja nende analüüsimiste tulemused uuenevad, siis aeg-ajalt toimub ka varasemalt sekveneeritud andmete kordusanalüüsimine ja uuendamine. Helsingi Ülikooli FIMM sekveneerimislabori kui kvaliteetse eksoomi sekveerimise teenusepakkuja kasutamine on heaks kiidetud TÜ Inimuuringute Eetikakomitee poolt. Kogu DNA, mida FIMM teenuslabor sekveneerimiseks ära ei kasutata saadetakse tagasi BSMI inimese geneetika õppetoolile hoiustamiseks nende biopangas. Patsiendi DNAd kasutatakse ka täiseksoomi sekveneerimisel leitud geenivariantide kinnitamiseks BSMI inimese geneetika õppetooli laboris sõltumatu meetodi, Sanger sekveneerimisega. Täiseksoomi toorandmeid hoiustame TÜ ülikooli serveris, millele ligipääs ja importimisõigus on vaid projekti andmete analüüsis vahetult osalevatel kaastöötajatel. Andmete teadustööks kasutamise ja publitseerimise õigus on uuringusse panustanud uurijatel ning peab olema kooskõlas vastutava uurija ja kliiniliste juhtiv-uurijatega. Eksooomi sekveneerimisel tuvastatud DNA variandid annoteeritakse kasutades ajakohast tarkvara (2022 on selleks VEP, https://www.ensembl.org/info/docs/tools/vep/index.html ; ja ANNOVAR, https://annovar.openbioinformatics.org/en/latest/ ). Annoteerimise eesmärgiks on anda igale geenivariandile taustainformatsioon, mida kasutades andmestik analüüsitakse tuvastamaks haigusseoselisd variandid. Geenivariantide patogeensuse hindamiseks kasutatakse ACMG ( The American College of Medical Genetics and Genomics) ja AMP ( The Association for Molecular Pathology) juhiseid ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kBHd5vFV","properties":{"formattedCitation":"(34)","plainCitation":"(34)","noteIndex":0},"citationItems":[{"id":235,"uris":["http://zotero.org/users/9406326/items/DYSE38C4"],"itemData":{"id":235,"type":"article-journal","abstract":"Disclaimer: These ACMG Standards and Guidelines were developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.","container-title":"Genetics in Medicine","DOI":"10.1038/gim.2015.30","ISSN":"1530-0366","issue":"5","journalAbbreviation":"Genet Med","language":"en","note":"Bandiera_abtest: a\nCg_type: Nature Research Journals\nnumber: 5\nPrimary_atype: Research\npublisher: Nature Publishing Group\nSubject_term: Genetic testing;Genetic variation;Medical genetics;Pathology\nSubject_term_id: genetic-testing;genetic-variation;medical-genetics;pathology","page":"405-423","source":"www.nature.com","title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","title-short":"Standards and guidelines for the interpretation of sequence variants","volume":"17","author":[{"family":"Richards","given":"Sue"},{"family":"Aziz","given":"Nazneen"},{"family":"Bale","given":"Sherri"},{"family":"Bick","given":"David"},{"family":"Das","given":"Soma"},{"family":"Gastier-Foster","given":"Julie"},{"family":"Grody","given":"Wayne W."},{"family":"Hegde","given":"Madhuri"},{"family":"Lyon","given":"Elaine"},{"family":"Spector","given":"Elaine"},{"family":"Voelkerding","given":"Karl"},{"family":"Rehm","given":"Heidi L."}],"issued":{"date-parts":[["2015",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (34) . Hindamise protsess põhineb rahvusvaheliselt kokku lepitud standarditel, toetudes erinevatele kliinilisele ja teaduslikele andmebaasidele (ClinVar, Human Protein Atlas jt.) ja ajakohastatud teaduskirjandusele. Hinnatakse konkreetse variandi patogeensust, kliiniliselt on olulised variandid, mis saavad hinnangu “patogeenne” või “tõenäoliselt patogeenne”. Lisaks kasutatakse analüüsis mudelipõhist statistilist lähenemist PSAP ( Population sampling Probability) , mis hindab, kui suure statistilise tõenäosusega leitud geenivariant võiks juhuslikult esineda (PSAP P ≤ 0,005) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XhA6xKru","properties":{"formattedCitation":"(35)","plainCitation":"(35)","noteIndex":0},"citationItems":[{"id":230,"uris":["http://zotero.org/users/9406326/items/FXX6MLZD"],"itemData":{"id":230,"type":"article-journal","abstract":"Donald Conrad and colleagues present a method, PSAP, for prioritizing potential Mendelian disease-causing variants in single human exomes using pathogenicity scores and observed allele frequencies in the unaffected population. They apply PSAP to cohorts of undiagnosed disease exomes and identify candidate disease variants for future study.","container-title":"Nature Genetics","DOI":"10.1038/ng.3697","ISSN":"1546-1718","issue":"12","journalAbbreviation":"Nat Genet","language":"en","note":"Bandiera_abtest: a\nCg_type: Nature Research Journals\nnumber: 12\nPrimary_atype: Research\npublisher: Nature Publishing Group\nSubject_term: Genomics;Medical genetics;Software\nSubject_term_id: genomics;medical-genetics;software","page":"1455-1461","source":"www.nature.com","title":"Genome-wide significance testing of variation from single case exomes","volume":"48","author":[{"family":"Wilfert","given":"Amy B."},{"family":"Chao","given":"Katherine R."},{"family":"Kaushal","given":"Madhurima"},{"family":"Jain","given":"Sanjay"},{"family":"Zöllner","given":"Sebastian"},{"family":"Adams","given":"David R."},{"family":"Conrad","given":"Donald F."}],"issued":{"date-parts":[["2016",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (35) . Patogeensuse hindamisel kasutatakse ka mõõdikut CADD ( Combined Annotation Dependent Depletion). CADD skoor kombineerib alernatiivsed in silico analüüsitulemused üheks mõõdikuks et hinnata geenivariandi võimalikku haigus-seoselisust ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"O1CBIXys","properties":{"formattedCitation":"(36)","plainCitation":"(36)","noteIndex":0},"citationItems":[{"id":241,"uris":["http://zotero.org/users/9406326/items/W5JILQ7J"],"itemData":{"id":241,"type":"article-journal","abstract":"Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection. Here we review the latest updates to CADD, including the most recent version, 1.4, which supports the human genome build GRCh38. We also present updates to our website that include simplified variant lookup, extended documentation, an Application Program Interface and improved mechanisms for integrating CADD scores into other tools or applications. CADD scores, software and documentation are available at https://cadd.gs.washington.edu.","container-title":"Nucleic Acids Research","DOI":"10.1093/nar/gky1016","ISSN":"1362-4962","issue":"D1","journalAbbreviation":"Nucleic Acids Res","language":"eng","note":"PMID: 30371827\nPMCID: PMC6323892","page":"D886-D894","source":"PubMed","title":"CADD: predicting the deleteriousness of variants throughout the human genome","title-short":"CADD","volume":"47","author":[{"family":"Rentzsch","given":"Philipp"},{"family":"Witten","given":"Daniela"},{"family":"Cooper","given":"Gregory M."},{"family":"Shendure","given":"Jay"},{"family":"Kircher","given":"Martin"}],"issued":{"date-parts":[["2019",1,8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} (36) . Tuvastatud võimalikke põhjuslikke geenivariante hinnatakse ükshavaal manuaalselt, vajadusel viiakse läbi haigus-seoselisust kinnitavad eksperimentaalsed katsed (e.g. kandidaatvariantide segregatsioon perekonnas, in vitro funktsionaalsed anaüüsid jne). Samuti rakendatakse nn. ‘matchmaking’ protsessi, mille eesmärk on leida sõltumatu(d) patsiendid, kelle puhul kehtib sama genotüüp-fenotüüp seos. 11. Uuritavate valim ja värbamise viisi kirjeldus. Uuritavate informeerimise ja nõusoleku vormid, ankeetide, küsitluste ja testide vormid esitada taotluse lisadena. Valimi suurus ja kontrollgruppide olemasolu 21 geenidoonorit , kontrollgrupp puudub . Kes värbab uuritavaid ja kuidas/kus/kelle poolt võetakse informeeritud nõusolek? (kui on asjakohane) Uuritavad on värvatud Eesti geenivaramu poolt, kus nad on andnud eelnevalt nõusoleku oma andmete töötlemiseks . Vastavalt geenidoonorite konfidentsiaalsuse printsiibile ei ole võimalik nende poole isiklikult pöörduda, et antud uuringu jaoks eraldi eraldi nõusolekut küsida. Kuidas ja kelle hulgast toimub uuritavate valik? Millised on uuritavate kaasamise või väljajätmise kriteeriumid? Eesti geenivaramu le on tehtud eelpäring idiopaatiliste viljatuse juhtude leidmiseks kriteeriumite alusel: Omavad diagnoosi E28.3 Täitnud terviseküsimustiku Vastanud küsimustele I 6.1 “millises vanuses menstruatsioonid lõppesid” vastusega &lt;40 aastat Vasatnud küsimusele menstruatsioonide lõppemise osas vastusega “menopaus” Eelpäringu andmetel (oktoober 2021, A. Valkna poolt) on vastavaid analüüsitud isikuid 21, kelle bioloogilist materjali (DNAd) ja terviseküsitlus e andmeid taotleme . Sekkumiste liik (füüsiline, vaimne või andmed, sh eriliiki isikuandmed) Taotleme Eesti geenivaramust bioloogilist materjal i (DNAd) ning terviseküsitlus t e vastuseid . Koormus uuritavale (kontaktivõtmise viisid, visiitide arv, uuringute tüüp ja arv, kutsete saatmise kordus jms) Lisakoormust geenidoonoritele ei teki . 12. Koeproovide väljastamine kolmandatele osapooltele (RNA, DNA, plasma vms) Mitme geenidoonori koeproove ja mis tüüpi koeproove väljastatakse? 21 geenidoonori genoomne DNA . Kui palju ühe geenidoonori kohta koeproove väljastatakse? 1 mikrogramm Kuhu koeproov väljastatakse (riik, asutuse nimetus, aadress)? Bio- ja Siirdemeditsiini Instituut, Tartu Ülikool, Eesti Ravila 19, 50411 Tartu, Eesti Mida tehakse järelejäänud koeproovidega (kas ülejääk hävitatakse või saadetakse tagasi)? Oleme küsinud minimaalse koguse DNAd (1 mikrogramm), mis on vajalik eksoomi sekveneerimiseks, kandidaatleidude kinnitamiseks ( absoluutselt vajalik ja elementaarne etapp monogeensete põhjuste uuringutes) ja vajadusel täiendavateks uuringuteks teiste DNA analüüsi meetoditega. Need uuringud toimuvad pikema periooodi vältel ja iga konkreetse juhu puhul erinevas ajaskaalas uuringuperioodi jooksul . Suure tõenäosusega kasutatakse enamikel juhtudel kogu saadud DNA alikvoot laboriuuringute käigus ära. Kui analüüsimisest jääb siiski bioloogilist materjali üle, siis tagastatakse see EGV-le peale plaanitud laboriuuringute lõppu 2032 aastal vastavalt uuringuplaanile (Tartu Ülikooli inimuuringute eetika komitee kooskõlastus 361/T-25). Bioloogilise materjali hoiustamine uurijate laboris (TÜ Bio- ja Siirdemeditsiini Instituudi inimese geneetika õppetooli biopangas) kogu uuringu perioodil võimaldab koheselt läbi viia geneetiliste leidude kinnitamist (e.g Sanger sekveneerimine) ja/või muid vajalikke molekulaarseid süva- uuringuid. Lahendamata jäänud POI juhtumite puhul saab rakendada uuringuperioodil uusi, pidevalt täienevaid , meetodeid . 13. Uuringu eetiliste aspektide analüüs (3600 tähemärki, kuni 2 lk). Kõik uuringud, mille objektiks on inimesed, peavad olema läbi viidud, arvestades eetilisi nõudeid, eelkõige autonoomia austamise, heategemise ja kahju vältimise ning õigluse printsiipe. ( https://www.coe.int/en/web/bioethics/guide-for-research-ethics-committees-members ). vt ka https://www.etag.ee/wp-content/uploads/2020/01/Eetika_Tabel_EST_2020.pdf 13 a Inimesed Abiküsimused Ei Jah Kas uurimisobjektiks on inimesed? X Uuringu kriteeriumitele vastavad analüüsitavad isikud on Eesti geenivaramu le andnud eelnevalt informeeritud nõusoleku oma andmete töötlemiseks. Uuringu läbiviijatel ei ole isiklikku kontakti geenidoonoritega . Kas uurimisobjektiks on haavatavad isikud või isikute grupid? Ei X Kas uurimisobjektiks on isikud, kes ei saa ise anda teadlikku nõusolekut uuringus osalemiseks (sh piiratud teovõimega isikud)? Ei X Kas uurimisobjektiks on alaealised? Ei X Kas uurimisobjektiks on patsiendid? X Uuringusse on kaasatud võimalikud idiopaatilise enneaegse munasarja puudulikkusega geenidoonorid Eesti geenivaramu st kaasatakse geenidoonorid , kes vastavad kriteeriumitele: Omavad diagnoosi E28.3 Täitnud terviseküsimustiku Vastanud küsimustele I 6.1 “millises vanuses menstruatsioonid lõppesid” vastusega &lt;40 aastat Vasatnud küsimusele menstruatsioonide lõppemise osas vastusega “menopaus” Geenidoonori d on Eesti geenivaramu le eelnevalt andnud nõusoleku oma andmete töötlemiseks. Kliiniliselt oluliste juhuleidude puhul edastatakse andmed Eesti geenivaramu le . Kliiniliselt olulisteks leidudeks on variandid, mis tehtud andmeanalüüsi ja ACMG ( The American College of Medical Genetics and Genomics) kriteeriumite alusel kategoriseeruvad „patogeenseteks” või „tõenäoliselt patogeenseteks” variantideks. Ebaselge kliinilise tähendusega variantide ( variant of unknown significance- VUS ) osas tagasisidet ei anta. Doonorite edasise nõustamise vajaduse osas tehakse otsus Eesti Geenivaramu vastava personali poolt. Kas uurimistöös kogutakse inimestelt bioloogilisi proove? Kas inimestelt võetud bioloogiliisi proove kavatsetakse eksportida kolmandasse riiki ( https://www.aki.ee/et/teenused-poordumisvormid/andmete-edastamine-valisriiki ) või importida neid teisest riigist Eestisse? X Taotleme Eesti geenivaramu lt bioloogilis t materjali (DNAd). Uuringus kasutatakse juba Eesti geenivaramu s olemasolevaid bioloogilisi proove. Täiseksoomide sekveneerimise ning andmete genereerimise teenus tellitakse Helsingi Ülikooli FIMM sekveneerimise tuumiklaborist , kellega on meie uurimisrühmal olnud pika-aegne koostöö . See t eenuslabor on DNA sekveneerimise ja genotüpiseerimise partneriks Helsingi Ülikooli Meilahti Haigla igapäevases kliinilises töös, seega on tagatud nii patsientide DNAde kui sekveneerimise andmete ohutu töötlemise, hoidmise ja transportimise kõrge kvaliteet. Kogu DNA, mida FIMM teenuslabor sekveneerimiseks ära ei kasutata saadetakse tagasi BSMI inimese geneetika õppetoolile hoiustamiseks nende biopangas. Täiseksoomi toorandmeid hoiustame TÜ ülikooli serveris, millele ligipääs ja importimisõigus on vaid projekti andmete analüüsis vahetult osalevatel kaastöötajatel. Helsingi Ülikooli FIMM täiseksoomi sekveneerimise teenuse kasutamine on heaks kiidetud ka TÜ Inimuuringute komitee loaga. Pärast uuringu lõppemist säilitatakse bioloogiline materjal TÜ BSMI inimese geneetika õppetooli biopangas . 13 b Isikuandmed ja andmestikud Ei Jah Kas uurimistöö käigus kogutakse või analüüsitakse isikuandmeid, sh eriliiki isikuandmeid? X Uurijad taotlevad Eesti geenivaramu st 21 geenidoonori terviseküsimustiku andmeid ( VT! Lisa 3. ) ning bioloogilist materjali (DNAd) . Uuringu kriteeriumitele vastavad geenidoonorid on Eesti geenivaramu le andnud eelnevalt informeeritud nõusoleku nende andmete töötlemiseks. Geeniuuringute läbiviimiseks on oluline patsiendi taustainformatsioon. Ilma terviseandmeteta ei ole võimalik teha lõplike järeldusi geenide võimaliku haigusseoselisuse kohta ega hinnata võimalikke kaasuvaid terviseriske. Uurijad taotlevad Eesti geenivaramu st andmeid kodeerit ult . U urijatel ei ole võimalik andmesubjekte uuringu ajal ega peale seda tuvastada. Nimesid, isikukoode ega muid isikut tuvastatavaid andmeid EGV geenidoonorite ja nende lähisugulaste kohta ei küsita. Andmeid säilitatakse Tartu Ülikooli turvatud serveris kuhu on ligipääs vaid vahetult uuringuga seotud kaastöötajatel. Saadud kliiniliselt olulised tulemused edastame Eesti geenivaramu le krüpteeritud kujul. Doonorite nõustamise vajaduse osas tehakse otsus Eesti geenivaramu vastava personali poolt. Kas uurimistöö hõlmab üksikisiku süsteemset jälgimist, tema andmeprofiili kogumist või töödeldakse suures ulatuses eriliiki ja/või tundlikke andmeid või kasutatakse (sekkuvaid) andmete töötlemise meetodeid varjatud viisil (nt elulemuse uuringud, jälgimine, järelevalve, audio ja video salvestamine, geo- positsioneerimine jne) või mistahes andmete töötlemise protsessi, mis võib kahjustab uuritavate õigusi ning vabadust? Ei X Kas uurimistöös analüüsitakse eelnevalt kogutud isikuandmeid? X Tao tleme andmeid Eesti geenivaramu st Vastavalt geenidoonorite konfidentsiaalsuse printsiibile ei ole võimalik nende poole isiklikult pöörduda. Geeniuuringute läbiviimiseks on oluline patsiendi taustainformatsioon. Ilma terviseandmeteta ei ole võimalik teha lõplike järeldusi geenide võimaliku haigusseoselisuse kohta ega hinnata võimalikke kaasuvaid terviseriske. Kas uurimistöös analüüsitakse avalikult kättesaadavaid andmeid? Ei X Kas kavatsetakse edastada isikuandmeid või võimaldada neile juurdepääs kolmandast riikidest ( https://www.aki.ee/et/teenused-poordumisvormid/andmete-edastamine-valisriiki )? X Täiseksoomi sekveneerimise teenusepakkujale isikuandmeid ei edastata. Bioloogiline materjal edastatakse kodeeritud kujul. Kas uurimistöö lõppedes toimub isikuandmete hävitamine/ anonüümimine? X Uurijad taotlevad Eesti geenivaramu st andmeid kodeeritud kujul . Uurijatel ei ole võimalik andmesubjekte uuringu käigus ega peale seda tuvastada. 13 c Teised eetilised küsimused Kas uurimistöö läbiviimine võib kaasa tuua eelpool kirjeldamata eetilisi riske? Ei X 14. Täita, kui uuring põhineb andmekogu ja/või andmeallika andmetel. Andmekogu ja/või andmeallika nimetus : Tartu Ülikooli genoomika instituut, Eesti geenivaramu Isikuandmete töötlemise eesmärk : analüüsida Eesti patsientide valimis enneaegse munasarja puudulikkuse (POI), korduvate raseduse katkemiste (KRK), loote väärarendite ja perinataalsete surmade monogeenseid põhjuseid ning tuvastada nende seisundite võimalikke ühiseid geneetilisi tegureid. Andmekoosseis ja periood, mille kohta andmed kogutakse (vajadusel lisana) Eesti geenivaramu t erviseküsitlus e andmed , DNA 1 µg. Uuringu lõppemise kuupäev 1. aprill 2052 (TÜ inimuuringute eetikakomitee kooskõlastus nr. 361/T-25) 15. Isikuandmete kaitse meetmete kirjeldus, sealhulgas andmete hoidmise, säilitamise, turvalisuse ja kustutamise kohta, sh andmete ja/või koodivõtme kustutamise kuupäev (kuni 1800 tähemärki, 1 lk). Kirjeldada ja põhjendada uuringu vajaduseks kogutud andmete säilitamist ja tähtaega. Uurijad taotlevad andmeid Eesti geenivaramu st kodeeritud . Peale uurimistöö lõppu (1. aprill 2052) on võimalik vastavaid andmeid kasutada edasistes teadustöö projektides saades vastavale projektile eetikakomitee kooskõlastus. Kirjeldada isikuandmete pseudonüümimise protsessi ja vahendeid. Andmeid taodeldakse Eesti geenivaramu st kodeeritud kujul. Kas kavatsetakse geenidoonorite isikuandmeid depseudonüümida? Geenidoonorite isiku andmeid ei depseudonüümita. Kas toimub isikuandmete transportimine ning kirjeldada, kuidas on tagatud andmete turvalisus. Uuringu kliiniliselt olulised geneetilised tulemused edastame Eesti geenivaramu sse krüpteeritud kujul. Kirjeldada, kuidas on andmed kaitstud loata või ebaseadusliku töötlemise eest. DNA analüüside andmeid säilitame TÜ turvatud serveris ja neile on ligipääs vaid vastutaval uurijal ja geneetiliste andmete analüüsiga seotud kaastöötajatel. Kinnitan, et kõik uuringu läbiviijad on teadlikud projekti läbiviimisega kaasnevatest eetilistest ja isikuandmete kaitsega kaasnevatest nõuetest. Vastutava uurija allkiri / digiallkiri / Taotluse esitamise kuupäev Taotluse EBIN ID (täidab hindaja) Lisadokumentide loetelu: Vastutava uurija CV Terviseküsimustik ( Väljastatud Eesti geenivaramu st A. Valkna päringuna 7. september 2021) Terviseküsimustikust 21 Eesti Geenivaramu geenidoonori kohta küsitavate andmete täpsustatud koosseis. TÜ Inimuuringute eetikakomitee k ooskõlastus nr. 361T-25 Kasutatud kirjandus ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1. ESHRE. Guideline on the management of premature ovarian insufficiency [Internet]. 2015 [tsiteeritud 29. november 2021]. Available at: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Management-of-premature-ovarian-insufficiency.aspx 2. Veitia RA. Primary ovarian insufficiency, meiosis and DNA repair. Biomed J. aprill 2020;43(2):115–23. 3. Lagergren K, Hammar M, Nedstrand E, Bladh M, Sydsjö G. The prevalence of primary ovarian insufficiency in Sweden; a national register study. 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Eesti bioeetika ja inimuuringute nõukogu taotlus " Idiopaatilise enneaegse munasarja puudulikkuse, korduvate raseduste katkemiste, loote väärarendite ja perinataalsete surmade geneetilised põhjused" (vastutav täitja prof. Maris Laan , Tartu Ülikool) Registreerimise kuupäev: 17.06.2022 Registreerimise number: 1.1-12/2178. LISA 3. Eesti Geenivaramu ( EGV ) tervise küsimustiku st ( ver . 2.6.14.486 (04.12.2012) andmete päring 21 uuritava geenidoonori kohta . A3. Milline on teie rahvus? B1. Kas Te teate, kes on Teie bioloogiline ema? [ ainult Jah/Ei vastus ILMA ema nime või isikukoodita ] B1.6 Kas Teie ema on elus ? B1.9 Milline oli Tema surma põhjus ? B1.10 Kas Teie emal on lisaks Teile veel lapsi ? [ ainult Jah/Ei vastus ILMA õdede-vendade nimede või isikukoodideta ] B2 . Kas Te teate, kes on Teie bioloogiline isa? [ ainult Jah/Ei vastus ILMA isa nime või isikukoodita ] B2.6 Kas Teie isa on elus? B2.9 Milline oli Tema surma põhjus? B2.10 Kas Teie isal on lapsi, keda seoses Teie emaga veel nimetatud ei ole? [ ainult Jah/Ei vastus ILMA õdede-vendade nimede või isikukoodideta ] B4 Kas Teil on bioloogilisi lapsi? [ ainult Jah/Ei vastus ILMA laste nimede või isikukoodideta ] E2.1-2.8 Tippsport [ kogu küsimuste blokk ] G1 Kas Te olete oma elus suitsetanud enamaks kui proovimiseks? G1.1 Kui vanalt Te hakkasite suitsetama? G1.2 Kas Te olete suitsetanud viimase 12 kuu jooksul? G1.3 Kui palju ja kui sageli olete Te viimase aasta, see on viimase 12 kuu jooksul, järgnevaid tubakatooteid tarvitanud? G1.4 Mitu aastat olete Te sellisel moel tubakatooteid tarvitanud? H1.2. Kui sageli Te keskmiselt alkohoolseid jooke tarvitate? I 1.1-10.6 Naiste tervis [ kogu küsimuste blokk ] K1 Milliseid haigusi on Teil diagnoositud? K1.1 Kas põete praegu haigust? K1.5 Kasvajalise haiguse spetsiifiline ravi K1.5.1 Kas haigus on ravitud? Kuidas haigus raviti? K1.5.2 Kirurgiline K1.5.3 Radioteraapia K1.5.4 Hormoonravi K1.5.5 Keemiaravi K1.5.6 Muu K1.7.1 Kas Teile on tehtud luu ulrahelidensitomeetriat ? K1.7.2 T-skoori väärtus K1.7.3 Kas Teile on tehtud luu DXA- densitomeetriat K1.7.4 T-skoori väärtus K1.9 Nägemislangus K3. Südamehaiguste lisaküsimused. L1 . Milliseid ravimeid Te regulaarselt tarvitate? L4 . Kas Teile on mõne haigusega seoses teostatud kirurgilisi operatsioone? M1 . Kas Teie emal või tema vanavanematel on diagnoositud järgnevaid haiguseid? M2 . Milliseid haigusi on Teie emal ja tema vanematel veel diagnoositud? M3 . Kas Teie isal või tema vanematel on diagnoositud järgnevaid haiguseid? M4 . Milliseid haigusi on Teie isal ja tema vanematel veel diagnoositud? N1 . Kui pikk Te olete ? N2 . Kui palju Te kaalute ? Soovime teada ka geenidoonori vanust kaasamise hetkel. Seda EGV küsimustiku meile kättesaadavas formaadis ei lei a . Eesti bioeetika ja inimuuringute nõukogu taotlus " Idiopaatilise enneaegse munasarja puudulikkuse, korduvate raseduste katkemiste, loote väärarendite ja perinataalsete surmade geneetilised põhjused" (vastutav täitja prof. Maris Laan , Tartu Ülikool) Registreerimise kuupäev: 17.06.2022 Registreerimise number: 1.1-12/2178. Vastused Eesti bioeetika ja inimuuringute nõukogu ( 14.06.2022 koosolek ) küsimustele . Esita n täiendatud taotlus e (eraldi dokument koos muudatuse kollasel taustal ning lisadega) koos vastustega küsimustele (allpool) . 1. Palume sõnastada tervikuuringu eesmärk ning eraldi EBINile esitatud uuringu osa uurimisküsimus ja hüpotees. Tervikuuringu eesmärgiks on analüüsida Eesti valimis idiopaatilise ehk seletamatu enneaegse munasarja puudulikkuse ( premature ovarian insufficiency , POI), korduvate raseduse katkemiste (KRK), loote väärarendite ja perinataalsete surmade monogeenseid põhjuseid ning tuvastada nende seisundite võimalikke ühiseid geneetilisi tegureid. EBINile tehtud taotlus e eesmärgiks on kaasata Eesti Geenivaramu POI sümptomite ja/või diagnoosiga geenidoonoreid suurendamaks ja võimendamaks Tartu ja Tallinna Naistekliinikutes (SA TÜK, AS ITK) tervikuuringusse kogut avat valimit. POI definitsioon: hüpergonadotroopse hüpogonadismi sündroomi, mille korral aktiivne munasarja talitlus lakkab enne 40. eluaastat ning mida iseloomustavad menstruatsioonihäired, tõusnud gonadotropiinide tase ja madal östradiooli tase. Uuringusse soovime kaasata konkreetsetele kriteeriumitele vastavad geenidoonorid, kes on Eesti Geenivaramusse eelnevalt andnud nõusoleku andemete töötlemiseks. Geenivaramu doonoritele kehtivad kriteeriumid: Omavad RHK-10 diagnoosi E28.3 (Primaarne munasarja puudulikkus) Vasatanud geenivararamus läbi viidud terviseküsitlusele Vastanud terviseküsimustikus küsimusele: “Millises vanuses menstruatsioonid lõppesid?” ning vastuseks vanus &lt;40 aastat Vastanud menstruatsioonide lõppemise põhjuse küsimusele vastusega “menopaus”. Geenivaramusse tehtud eelpäringu andmetel (oktoober 2021, Anu Valkna ) on vastavate kriteeriumite alusel valimi suuruseks 21 geeni doonorit. EBIN tehtud taotluse uuringuküsimus ja hüpotees vastavad tervikuuringule. EBIN taotlusega seotud u urimisküsimused: Millised on idiopaatilise POI monogeensed ehk ühest geeniveast tingitud põhjused ? Milli sed on naiste reproduktiivhäirete ühised ehk pleiotroopsed monogeensed põhjused ? K uidas saadud teadmisi oleks võimalik rakendada kliinilisse praktikasse? Hüpotees id : Idiopaatili se PO I juhud on põhjustatud veel teadmata monogeensetest geneetilistest põhjustest POI, KRK, loote väärarendite ja perinataalsete surmade geneetiline etioloogia on osaliselt kattuv ja selle arvesse võtmine tõhustab patsientide kliinilist käsitlust 2. Igasugune andmete kogumine peab olema eesmärgipärane ja vastama minimaalsuse nõudele. Sellest tulenevalt on EBINil küsimus - millega on põhjendatud EGV terviseküsimustiku kõikide andmete küsimine 21 GD kohta (sh lähisugulaste isikukoodid, haigused jms)? Vabandame, et esitatud taotlus oli ebaselge . Me ei ole soovinud küsi da ei isikukoode ega muid isikut tuvastatavaid andmeid EGV geenidoonorite ja nende lähisugulaste kohta. Uuringus kasutame analüüsitavate geenidoonorite Eesti Geenivaramu poolt kodeeritud andmeid. Lähtudes uuringu tüübist on u uringu meeskonna eesmärgiks saada geenidoonorite kaasamisel nende poolt täidetud EGV küsimusti kus ( ver . 2.6.14.486 ; kuupäev 04.12.2012) sisalduvad asjakohased terviseandmeid , et toetada uute geneetiliste leidude interpreteerimis t . Vastavalt nõukogu soovitusele on uuringumeeskond vaadanud üle küsimused lähtudes uuringu eesmärkide st ning minimaalsuse nõude st . Küsimused on täpsustatud punktis 3 (allpool). 3. Soovitame läbi mõelda ja esitada nõukogule terviseküsimustikust küsitavate andmete täpsustatud koosseis. EGV küsimustiku st ( ver . 2.6.14.486 (04.12.2012) soovime 21 uuritava geenidoonori kohta teavet : A3. Milline on teie rahvus? B1. Kas Te teate, kes on Teie bioloogiline ema? [ ainult Jah/Ei vastus ILMA ema nime või isikukoodita ] B1.6 Kas Teie ema on elus ? B1.9 Milline oli Tema surma põhjus ? B1.10 Kas Teie emal on lisaks Teile veel lapsi ? [ ainult Jah/Ei vastus ILMA õdede-vendade nimede või isikukoodideta ] B2 . Kas Te teate, kes on Teie bioloogiline isa? [ ainult Jah/Ei vastus ILMA isa nime või isikukoodita ] B2.6 Kas Teie isa on elus? B2.9 Milline oli Tema surma põhjus? B2.10 Kas Teie isal on lapsi, keda seoses Teie emaga veel nimetatud ei ole? [ ainult Jah/Ei vastus ILMA õdede-vendade nimede või isikukoodideta ] B4 Kas Teil on bioloogilisi lapsi? [ ainult Jah/Ei vastus ILMA laste nimede või isikukoodideta ] E2.1-2.8 Tippsport [ kogu küsimuste blokk ] G1 Kas Te olete oma elus suitsetanud enamaks kui proovimiseks? G1.1 Kui vanalt Te hakkasite suitsetama? G1.2 Kas Te olete suitsetanud viimase 12 kuu jooksul? G1.3 Kui palju ja kui sageli olete Te viimase aasta, see on viimase 12 kuu jooksul, järgnevaid tubakatooteid tarvitanud? G1.4 Mitu aastat olete Te sellisel moel tubakatooteid tarvitanud? H1.2. Kui sageli Te keskmiselt alkohoolseid jooke tarvitate? I 1.1-10.6 Naiste tervis [ kogu küsimuste blokk ] K1 Milliseid haigusi on Teil diagnoositud? K1.1 Kas põete praegu haigust? K1.5 Kasvajalise haiguse spetsiifiline ravi K1.5.1 Kas haigus on ravitud? Kuidas haigus raviti? K1.5.2 Kirurgiline K1.5.3 Radioteraapia K1.5.4 Hormoonravi K1.5.5 Keemiaravi K1.5.6 Muu K1.7.1 Kas Teile on tehtud luu ulrahelidensitomeetriat ? K1.7.2 T-skoori väärtus K1.7.3 Kas Teile on tehtud luu DXA- densitomeetriat K1.7.4 T-skoori väärtus K1.9 Nägemislangus K3. Südamehaiguste lisaküsimused. L1 . Milliseid ravimeid Te regulaarselt tarvitate? L4 . Kas Teile on mõne haigusega seoses teostatud kirurgilisi operatsioone? M1 . Kas Teie emal või tema vanavanematel on diagnoositud järgnevaid haiguseid? M2 . Milliseid haigusi on Teie emal ja tema vanematel veel diagnoositud? M3 . Kas Teie isal või tema vanematel on diagnoositud järgnevaid haiguseid? M4 . Milliseid haigusi on Teie isal ja tema vanematel veel diagnoositud? N1 . Kui pikk Te olete ? N2 . Kui palju Te kaalute ? Soovime teada ka geenidoonori vanust kaasamise hetkel. Seda EGV küsimustiku meile kättesaadavas formaadis ei leia. Taotlusele lisatud Lisa 3. Eesti Geenivaramu (EGV) tervise küsimustikust ( ver . 2.6.14.486 (04.12.2012) andmete päring 21 uuritava geenidoonori kohta . 4. Mis põhjusel ei tagastata analüüsimisest ülejäävat bioloogilist materjali EGVsse ? Inimgeeniuuringute seadusest tulenevalt peavad geenidoonorite bioloogilised proovid olema kas hävitatud või tagastatud EGV- le , kellel on kohustus neid säilitada. Oleme küsinud minimaalse koguse DNAd (1 mikrogramm), mis on vajalik eksoomi sekveneerimiseks , kandidaatleidude kinnitamiseks (absoluutselt vajalik ja elementaarne etapp monogeensete põhjuste uuringutes ) ja vajadusel täiendavateks uuringuteks teiste DNA analüüsi meetoditega. Need uuringud toimuvad pikema perioodi vältel ja iga konkreetse juhu puhul erinevas ajaskaalas uuringuperioodi jooksul . Suure tõenäosusega kasutatakse enamikel juhtudel kogu saadud DNA alikvoot laboriuuringute käigus ära. Kui analüüsimisest jääb siiski bioloogilist materjali üle, siis tagastatakse see EGV- le peale plaanitud laboriuuringute lõppu 2032 aastal vastavalt uuringuplaanile (Tartu Ülikooli inimuuringute eetika komitee kooskõlastus 361/T-25). Bioloogilise materjali hoiustamine uurijate laboris (TÜ Bio - ja Siirdemeditsiini Instituudi inimese geneetika õppetooli biopangas ) kogu uuringu perioodil võimaldab koheselt läbi viia geneetiliste leidude kinnitamist ( e.g Sanger sekveneerimine ) ja/või muid vajalikke molekulaarseid süva-uuringuid. Lahendamata jäänud POI juhtumite puhul saab rakendada uuringuperioodil uusi, pidevalt täienevaid, meetodeid. 5. Avalduses märgitud, et uuringut teostatakse kuni aprill 2032, samas pseudonüümitud andmete säilitamine toimub aastani 2052. Punktis 12 märgitud, et uurimisprojekt kestab kuni 2052. Kas ja kuidas kasutatakse andmeid 2032-2052? 6. Miks on vajalik isikuandmete säilitamine kuni aastani 2052, ei ole selgelt põhjendatud. 7. Kas ja kuidas aastal 2052 andmed/ andmekandjad hävitatakse? Palun põhjendage nii pikka andmete säilitamise tähtaega? Vabandame, et esitatud taotlus oli ebaselge . EGV 21 geenidoonorit moodustavad tervikuuringu valimist ühe (väiksema) osa. T ervikuuringus kaasame patsiente kliinikutes ja sellisel juhul on pseudonüümimine ja koodi pika-ajaline säilitamine haigusseoseliste geenivariantide uuringu läbiviimisel ja patsientide (ja vajadusel /nõusolekul nende perede) tagasisidestamisel oluline . Eesti g eenivaramu geenidoonorite isikuandmeid taotleme kodeeritud kujul (terviseküsimustikust soovitud info saamine VT! punkt 3) . U uringu meeskonnal ei ole nende isikute (ega nende pereliikmete) identifitseerimiseks vajalik ke isikukoode, nimesid või muid isikuandme i d. EGV juhtude puhul puudub uurijatel p seudonüümimise võti , sest uuringumeeskond taotleb andmeid juba kodeeritult. G eenidoonorite andmete kasutamise ja säilitamise osas ei ole erinevust 2022-2032 ja 2032-2052 . Säilitatavad EGV geenidoonorite andmed: EGV geenidoonori Eesti Geenivaramus kodeeritud kood terviseküsimustiku andmed ILMA isikukoodide või nimedeta (VT! ülal punkt 3) uuringu käigus kogutud geneetilised andmed Uuringumeeskond säilitab tervise - ja geneetilised andmeid kodeeritud kujul. Kommentaar tervikuuringu kohta (Tartu Ülikooli inimuuringute eetika komitee kooskõlastus 361/T-25) : Enamik käimasoleva tervikuuringu patsiente kaasatakse Eesti Naistekliinikutes. T ervikuuringu pseudonüümimise koodivõtme hävitamine toimub 2052 . Peale koodivõtme kustutamist säilivad andmed anonümiseeritult tähtajatult. T ervikuuringu kestus kuni 2052 a. on määratud ja kooskõlastatud , et oleks võimalik läbi viia kaasatud juhtude reproduktiivse tervise häirete ja sellega seotud üldtervise riskide pikaajalisi jätku - ja täiendavaid uuringud vähemalt kaasatud patsientide reproduktiivse ea lõpuni . Aja jooksul teadmised geneetikast täienevad, pikem säilitamine võimaldab ka lahendamata juhtude andmeid analüüsida vastavalt uuenenud teadmistele ning teha uusi järeldusi leitud geenileidude osas. Kuna antud uurimistöö keskendub geneetilistele leidudele, siis võimaldab Naistekliinikutes kaasatud patsientide pseudonüümimise võtme säilitamine kutsuda uuringusse vajadusel pikema perioodi jooksul ka erinevatest põlvkondadest pereliikmeid. Monogeenste haiguste geneetiliste põhjuste tuvastamisel on olnud laiendatud pereko nna põhine uuring peamine võtmemeetod juba alates 80ndates aastatest. Kliinikutes kogutud valmini pseudonüümitud andmete olemasolu võimaldab käivitada vajadusel ka täiendavaid uurimistöö põhieesmärkidega seotud projekt e ja jätku- uuringu id. Igal konkreetsel juhul taotleme TÜ inimuuringute eeti k akomitee kooskõlastus t . EGV geenidoonorite puhul laiemaid uuringuid rakenda ei saa, sest kõik andmed jõuavad uurijateni kodeeritud kujul ja saadud geneetilisi leide ei saa ka t agasi sidestada. Aga kuna EGV doonorid on osa valimist, siis nende andmete säilitami ne sarnaselt kliinikutes kaasatud juhtudega võimaldab suurendad a tervikuuringus kogutavat andmestikku ja tugevdada üldisemalt genotüüp-fenotüüp analüüside võimsust. 2052 a. ei hävitata ei andmeid ega andmekandjaid. Andmete kasutamine toimub anonümiseeritud kujul. 8. Nõukogu soovitab kaaluda andmete säilitamise lühemat tähtaega ja uute uuringute puhul vajadusel pöörduda andmete kasutamise loa saamiseks uuesti nõukogu poole. Tartu Ülikooli inimuuringute eetika komitee (otsus 361/T-25 ) on kooskõlastanud tervikuuringu läbiviimise kuni 01.04.2052. Peame oluliseks kogu tervikuuringu materjali ühtemoodi säilitamist , sest eesmärk naiste reproduktiivhäirete uute monogeens e te põhjuste tuvastamiseks on ju sama, sõltumata kas patsiendid on kaasatud Naistekliinikutes või tuvastatud Eesti Geenivaramu geenidoonorite seast. Lugupidamisega , Maris Laan vastutav täitja /allkirjastatud digitaalselt/ Saatja: Maris Laan <[email protected]> Saadetud: 23.07.2022 17:05 Adressaat: SM Info <[email protected]> Koopia: Anu Valkna <[email protected]>; Kristiina Rull <[email protected]> Teema: parandustega taotlus (Maris Laan) Manused: Avaldus Eesti bioeetika ja inimuuringute nõ ukogule_Maris Laan_parandustega.asice tere käesolevaga saadan paranduste ja täiendtustega taotluse. Suvetervitustega, Maris Laan inimese geneetika professor, akadeemik Bio- ja Siirdemeditsiini Instituut Ravila 19, 50411 Tartu Kontakt: 53495258; 7375008 Email: [email protected]