☆ 4.7 Article

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

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2019)

Journal

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM

Volume 104, Issue 8, Pages 3049-3067

Publisher

ENDOCRINE SOC

DOI: 10.1210/jc.2019-00248

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Funding

National Human Genome Research Institute (NHGRI)
National Heart Lung and Blood Institute (NHBLI) [UM1 HG006542]
National Institute of Neurologic Disorders and Stroke (NINDS) [R35NS105078]
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) [91617021]
NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation
Muscle Study Group (MSG)

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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 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.

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Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency

Bushra Gorsi, Edgar Hernandez, Marvin Barry Moore, Mika Moriwaki, Clement Y. Chow, Emily Coelho, Elaine Taylor, Claire Lu, Amanda Walker, Philippe Touraine, Lawrence M. Nelson, Amber R. Cooper, Elaine R. Mardis, Aleksander Rajkovic, Mark Yandell, Corrine K. Welt

Summary: The study identified candidate causative variants in women with POI through whole exome sequencing (WES) and found gene sets with increased burden of deleterious variants. Seven new risk genes for POI were discovered with functional evidence, expanding the genetic architecture of heterozygous rare gene variants causing risk for POI.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2022)