ArticleThe Journal of clinical endocrinology and metabolism2025
A Tiered Approach to Exome Sequencing Analysis in Early-Onset Primary Ovarian Insufficiency.
Article in The Journal of clinical endocrinology and metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Article
- A Tiered Approach to Exome Sequencing Analysis in Early-Onset Primary Ovarian Insufficiency.The Journal of clinical endocrinology and metabolism · 2025Article
- Novel variants associated with premature ovarian insufficiency in Russian adolescents.Frontiers in endocrinology · 2025Article
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9 authors.
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Abstract
contextEstablishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging.
objectiveWe 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.
resultsA 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.
conclusionThe 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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