A Tiered Approach to Exome Sequencing Analysis in Early-Onset Primary Ovarian Insufficiency

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CONTEXT: Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging. OBJECTIVE: We aimed to elucidate the genetic architecture of EO-POI in a unique, large cohort. Young women with EO-POI (n = 149; n = 31 familial, n = 118 sporadic) attending a specialist reproductive unit were included. Exome sequencing was performed. After filtering, variants were retained that were: (1) rare/novel (minor allele frequency <0.01%); (2) predicted pathogenic/likely pathogenic; and (3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n = 69); Category 2, variants in other POI-associated genes (n = 355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes. RESULTS: A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSMC3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n = 75/118) women had a variant identified: 21.2% (n = 25) Category 1; 42.4% (n = 50) Category 2. Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1. CONCLUSION: The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.

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