Exome sequencing of a primary ovarian insufficiency cohort reveals common molecular etiologies for a spectrum of disease

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dc.authoridBülent Hacıhamdioğlu / 0000-0001-7070-6429
dc.authorscopusidBülent Hacıhamdioğlu / 22134579900
dc.authorwosidBülent Hacıhamdioğlu / GBK-6773-2022
dc.contributor.authorJolly, Angad
dc.contributor.authorBayram, Yavuz
dc.contributor.authorTuran, Serap
dc.contributor.authorAycan, Zehra
dc.contributor.authorTos, Tülay
dc.contributor.authorAbalı, Zehra Yavaş
dc.contributor.authorLupski, James R.
dc.contributor.authorHacıhamdioğlu, Bülent
dc.date.accessioned2020-08-30T20:06:39Z
dc.date.available2020-08-30T20:06:39Z
dc.date.issued2019
dc.departmentİstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümüen_US
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.en_US
dc.description.sponsorshipNational Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart Lung and Blood Institute (NHBLI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; National Institute of Neurologic Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986, U54HG003273]; Howard Hughes Medical Research Fellows Program; Baylor College of Medicine Medical Scientist Training Program; Clinical Research Training Scholarship in Neuromuscular Disease; American Academy of Neurology (AAN); American Brain Foundation (ABF); Netherlands Organization for Scientific Research (ZonMW Veni)Netherlands Organization for Scientific Research (NWO) [91617021]; NARSAD Young Investigator Grant from the Brain & Behavior Research FoundationNARSAD; Muscle Study Group (MSG)en_US
dc.description.sponsorshipThis study was supported in part by the National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542 to J.R.L.); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273 to R.A.G.), and National Institute of Neurologic Disorders and Stroke (NINDS; R35NS105078 to J.R.L.). J.E.P. was supported by NHGRI K08 HG008986. A.J. was supported in part by the Howard Hughes Medical Research Fellows Program and the Baylor College of Medicine Medical Scientist Training Program. D. P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology (AAN), American Brain Foundation (ABF), and Muscle Study Group (MSG). T.S.B. was supported by the Netherlands Organization for Scientific Research (ZonMW Veni, Grant 91617021) and by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation.en_US
dc.identifier.citationJolly, A., Bayram, Y., Turan, S., Aycan, Z., Tos, T., Abali, Z. Y., … Lupski, J. R. (2019). Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 104(8), 3049–3067. https://doi.org/10.1210/jc.2019-00248en_US
dc.identifier.doi10.1210/jc.2019-00248en_US
dc.identifier.endpage3067en_US
dc.identifier.issn0021-972Xen_US
dc.identifier.issn1945-7197en_US
dc.identifier.issue8en_US
dc.identifier.pmid31042289en_US
dc.identifier.scopus2-s2.0-85068196374en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage3049en_US
dc.identifier.urihttps://doi.org/10.1210/jc.2019-00248
dc.identifier.urihttps://hdl.handle.net/20.500.12713/585
dc.identifier.volume104en_US
dc.identifier.wosWOS:000482558500001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorHacıhamdioğlu, Bülenten_US
dc.language.isoenen_US
dc.publisherEndocrine Socen_US
dc.relation.ispartofJournal of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleExome sequencing of a primary ovarian insufficiency cohort reveals common molecular etiologies for a spectrum of diseaseen_US
dc.typeArticleen_US

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