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Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease

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dc.contributor.authorBEREKET, ABDULLAH
dc.contributor.authorsJolly, Angad; Bayram, Yavuz; Turan, Serap; Aycan, Zehra; Tos, Tulay; Abali, Zehra Yavas; Hacihamdioglu, Bulent; Akdemir, Zeynep Hande Coban; Hijazi, Hadia; Bas, Serpil; Atay, Zeynep; Guran, Tulay; Abali, Saygin; Bas, Firdevs; Darendeliler, Feyza; Colombo, Roberto; Barakat, Tahsin Stefan; Rinne, Tuula; White, Janson J.; Yesil, Gozde; Gezdirici, Alper; Gulec, Elif Yilmaz; Karaca, Ender; Pehlivan, Davut; Jhangiani, Shalini N.; Muzny, Donna M.; Poyrazoglu, Sukran; Bereket, Abdullah; Gibbs, Richard A.; Posey, Jennifer E.; Lupski, James R.
dc.date.accessioned2022-03-14T10:04:28Z
dc.date.available2022-03-14T10:04:28Z
dc.date.issued2019-08-01
dc.description.abstractContext: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hyper-gonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. Objective: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. Design, Setting, and Participants: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. Results: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. Conclusions: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.
dc.identifier.doi10.1210/jc.2019-00248
dc.identifier.eissn1945-7197
dc.identifier.issn0021-972X
dc.identifier.pubmed31042289
dc.identifier.urihttps://hdl.handle.net/11424/244005
dc.identifier.wosWOS:000482558500001
dc.language.isoeng
dc.publisherENDOCRINE SOC
dc.relation.ispartofJOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectMUTATIONS
dc.subjectGENE
dc.subjectFAILURE
dc.subjectIDENTIFICATION
dc.subjectVARIANTS
dc.subjectPROTEIN
dc.subjectREARRANGEMENTS
dc.subjectHOP2-MND1
dc.subjectMECHANISM
dc.subjectINSIGHTS
dc.titleExome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease
dc.typearticle
dspace.entity.typePublication
local.avesis.id4d00d61b-9745-450f-9d95-fbaac5d134bd
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages19
local.journal.quartileQ1
oaire.citation.endPage3067
oaire.citation.issue8
oaire.citation.startPage3049
oaire.citation.titleJOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
oaire.citation.volume104
relation.isAuthorOfPublication669e9474-4e39-453f-a4bc-4ede9cb5abac
relation.isAuthorOfPublication.latestForDiscovery669e9474-4e39-453f-a4bc-4ede9cb5abac

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