SFEIES24 Oral Poster Presentations Oral Posters 4 - Endocrinology 2 (4 abstracts)
A tiered, evidence-based approach to exome sequencing analysis in early-onset primary ovarian insufficiency
Sinead McGlacken-Byrne 1,2,3 , Jenifer P Suntharalingham 1 , Miho Ishida 1 , Federica Buonocore 1 , Ignacio Del Valle 1 , Antoinette Cameron-Pimblett 2 , UCL Genomics 4 , Mehul T. Dattani 1,3 , John Achermann 1 & Gerard S. Conway 2
1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; 2Institute for Women’s Health, University College London, London, United Kingdom; 3Department of Paediatric Endocrinology, Great Ormond Street Hospital, London, United Kingdom; 4UCL Genomics, Zayed Centre for Research, University College London, London, United Kingdom
Background: Sequencing of Primary Ovarian Insufficiency cohorts have identified variants in >100 “POI genes” in up to 50% of women but establishing pathogenicity is challenging. Early-onset POI (EO-POI; adolescents) may have a distinct genetic profile.
Methods: We performed exome sequencing (Nonacus) in an EO-POI cohort. Filtering (QCI) retained variants which were 1) rare/novel (MAF<0.01%), 2) predicted pathogenic in silico, 3) enriched in the cohort compared to gnomAD v4.0 controls; and 4) pathogenic/likely pathogenic (ACMG). Further filtering used three categories: 1) variants in genes on the Genomics England Primary Ovarian Insufficiency PanelApp; 2) variants in other genes previously associated with POI; and 3) homozygous variants.
Results: A total of 149 women with EO-POI were recruited (31 familial POI, 17 kindreds, 8 consanguineous; 118 sporadic POI; 81.2% (n = 121) primary amenorrhea). Of 17 familial POI kindred, 11 (64.7%) had a Category 1 or 2 variant (n = 6 Category 1: STAG3, MCM9, PSCM3IP, YTHDC2, ZSWIM7 (homozygous) and POLR2C (heterozygous); n = 5 Category 2: NLRP11 and PRKD1 (heterozygous), PLEC, IGSF10, KMT2A (homozygous), PDE3A, POLR2H, MSH6, CLPP (polygenic)). A total of 65.3% (n = 77) women with sporadic POI had a Category 1 or 2 variant (20.3% (n = 24) Category 1 and 42.4% (n = 50) Category 2; 30.9% heterozygous, 9.4% homozygous, 21.8% polygenic). Most heterozygous variants were present in gnomAD controls. The cohort was then screened for Category 3 variants, revealing 10 novel POI candidate genes in 8 women. These included genes with animal gonadal insufficiency models (PCIF1, DND1, MEF2A, TGFBR1), DNA repair genes (XRCC1, MMS22L, RXFP3), mitochondrial genes (PPAN, CLUH, COQ10B, MRPS14), and others (C4orf33, ARRB1).
Discussion: Using a tiered, evidence-based approach, we characterise the genetic landscape of EO-POI as complex and frequently multigenic. The pathogenicity of single heterozygote variants in EO-POI is often uncertain. Autosomal recessively inherited, monogenic POI accounts for a distinct EO-POI subset. We propose novel POI candidate genes.
Volume 104
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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