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

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 8; pp. 3049 - 3067
• Main Authors: Jolly, Angad, Bayram, Yavuz, Turan, Serap, Aycan, Zehra, Tos, Tulay, Abali, Zehra Yavas, Hacihamdioglu, Bulent, Coban Akdemir, Zeynep Hande, 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
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.08.2019; Copyright Oxford University Press; Oxford University Press
• Subjects: Amenorrhea; Cell Cycle Proteins - genetics; Clinical s; Cohort Studies; Consanguinity; Development and progression; DNA Helicases - genetics; DNA-Binding Proteins - genetics; Environmental factors; Etiology; Family; Female; Galactosemia; Gene Frequency; Genes; Genetic analysis; Genetic disorders; Genetic diversity; Genomics; Heterozygosity; Humans; Hypogonadism; Hypogonadism - genetics; Hypothalamus; Immunoglobulins - genetics; Medical colleges; Medical research; Medicine, Experimental; Meiosis; Menopause; Minichromosome Maintenance Proteins - genetics; Polygenic inheritance; Primary Ovarian Insufficiency - etiology; Primary Ovarian Insufficiency - genetics; Recombination; Whole Exome Sequencing; Texas
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2019-00248

Abstract 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. Exome sequencing was used to investigate genes and mutational mechanisms contributing to primary ovarian insufficiency, and to gain insights into disease biology and underlying pathophysiology.