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

TitleExome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsJolly, A, Bayram, Y, Turan, S, Aycan, Z, Tos, T, Abali, ZYavas, Hacihamdioglu, B, Akdemir, ZHande Coba, Hijazi, H, Bas, S, Atay, Z, Guran, T, Abali, S, Bas, F, Darendeliler, F, Colombo, R, Barakat, TStefan, Rinne, T, White, JJ, Yesil, G, Gezdirici, A, Gulec, EYilmaz, Karaca, E, Pehlivan, D, Jhangiani, SN, Muzny, DM, Poyrazoglu, S, Bereket, A, Gibbs, RA, Posey, JE, Lupski, JR
JournalJ Clin Endocrinol Metab
Date Published2019 Aug 01
KeywordsCell Cycle Proteins, Cohort Studies, DNA Helicases, DNA-Binding Proteins, Exome Sequencing, Female, Gene Frequency, Humans, Hypogonadism, Immunoglobulins, Minichromosome Maintenance Proteins, Primary Ovarian Insufficiency

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic 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.

Alternate JournalJ Clin Endocrinol Metab
PubMed ID31042289
PubMed Central IDPMC6563799
Grant ListR35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States

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