IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)
Advancing the genetic understanding of differences of sex development through whole genome sequencing
Gabby Atlas 1,3 , Jocelyn van den Bergen 1 , Gorjana Robevska 1 , Katrina Bell 1,2,4 , Elena Tucker 1,2 , Michele O’Connell 1,3 , Tiong Tan 1,4 , Nitzan Gonen 5 , Andrew Sinclair 1,2 & Katie Ayers 1,2
1Murdoch Children’s Research Institute; 2University of Melbourne; 3Royal Children’s Hospital, Melbourne; 4Victorian Clinical Genetics Services; 5Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel
Background/Aims: Currently a genetic diagnosis is found for up to 40-50% for individuals with a difference of sex development (DSD), indicating that there are likely other genomic aetiologies that need to be considered. This study aimed to improve the rates of genetic diagnoses for a cohort of individuals with DSD using whole genome sequencing (WGS), and develop insights into the utility of WGS for rare disease cohorts.
Methods: Individuals with severe forms of DSD such as 46,XY gonadal dysgenesis, who were undiagnosed after previous genomic testing (whole exome sequencing or targeted gene panel) were identified from the Reproductive Development laboratory group’s biobank. Previous data were reanalysed with an updated gene list, including undertaking an analysis of copy number variants (CNVs) using a locally developed CNV-caller. Whole genome sequencing (Illumina DNA, PCR-free with ~30x post alignment 2x150bp NovaSeq 6000 sequencing) was performed for 76 individuals, including 27 affected probands and their family members. Analysis and variant curation was undertaken, focusing on 138 diagnostic and candidate genes (and their surrounding genomic regions, as well as introns) known to be associated with DSD. Identified variants (likely pathogenic and pathogenic) were confirmed with Sanger Sequencing, and functional work undertaken to assist with classification.
Results: CNV analysis revealed an individual with a WT1 deletion, not previously identified through standard analysis of whole exome sequencing. Whole genome sequencing yielded a cohort of 3 individuals with loss-of-function variants in PPP1R12A, as well as a variant of uncertain significance in DAAM2. Additionally, we have identified a variant in a potential enhancer of a key DSD gene, NR5A1, in a family with two affected individuals (sisters with 46,XY gonadal dysgenesis). Luciferase assays showed a reduction in activity in the variant compared to wild type.
Conclusion: This work has identified the activity of an enhancer upstream of NR5A1, with reduced NR5A1 expression being a proposed reason for gonadal dysgenesis in these individuals. Additionally, the benefit of reanalysis of genomic data with new technologies and new gene lists is shown. Analysis of this first cohort of WGS has led to insights on looking at regions upstream of key DSD genes, which will guide future analysis approaches for WGS in rare disease.
Volume 118
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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