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 May 01

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75-90% of individuals with hypergonadotropic hypogonadism (HH) 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 non-syndromic single gene disorders suggesting POI represents a complex trait.

OBJECTIVE: To characterize the contribution of known disease genes to POI and identify novel 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 5 families with predicted deleterious variants in novel disease genes (IGSF10, MND1, MRPS22, and SOHLH1). Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity (AOH) 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, re-affirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multi-locus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

Alternate JournalJ. Clin. Endocrinol. Metab.
PubMed ID31042289