IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)
Refining the upstream SOX9 regulatory landscape through whole-genome sequencing in 46,XY complete gonadal dysgenesis
Hannes Syryn 1 , Julie Van de Velde 1,2 , Matthias Van Heetvelde 1 , Charlotte Matton 1 , Cécile Brachet 3 , Julie Fudvoye 4 , Sara Touzani 5 , Willem Staels 6 , Anne Rochtus 7 , Marieke den Brinker 8 , Dominique Beckers 9 , Sophie Lambert 10 , Martine Cools 2 & Elfride De Baere 1
1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; 2Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; 3Pediatric Endocrinology Clinic, Université Libre de Bruxelles (ULB), Brussels, Belgium; 4Department of Pediatrics, Liège University Hospital, Liège, Belgium; 5Pediatric Endocrinology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium; 6Division of Pediatric Endocrinology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; 7Department of Pediatric Endocrinology, University Hospitals Leuven, Leuven, Belgium; 8Department of Paediatric Endocrinology & Diabetology, University of Antwerp, Antwerp, Belgium; 9Pediatric Endocrinology and Diabetology, CHU-UCL Namur, Yvoir, Belgium; 10Department of Paediatric Endocrinology, Clinique CHC Montlégia, Liège, Belgium
Background: A genetic diagnosis in differences of sex development (DSD) can currently be made in about 30% of patients. New causal genes are reported only sporadically and account for very few cases, suggesting an important contribution of non-coding variants. Precise regulation of SOX9 is essential for human testis determination, and pathogenic variants in the coding region have been reported in 46,XY gonadal dysgenesis. In addition, copy-number variants affecting distal enhancers upstream of SOX9 have been described in cases of 46,XY complete gonadal dysgenesis (CGD), suggesting an important role of non-coding regulatory elements.
Methods: We performed whole-genome sequencing (WGS) in a cohort of 16 unrelated individuals with DSD, including 7 with CGD, 1 with partial gonadal dysgenesis, 5 with ovotesticular DSD, and 3 with primary ovarian insufficiency, following negative exome sequencing. Structural variants in the upstream SOX9 regulatory region were analyzed. The minimal critical interval was refined by integrating previously reported pathogenic variants with public epigenomic datasets, including DNase I hypersensitivity, ATAC-seq, and ChIP-seq data, as well as publicly available single-cell transcriptomic and epigenomic datasets from human gonadal tissues.
Results: Two out of seven individuals with 46,XY CGD were found to carry heterozygous deletions located 644-345kb and 639-500kb upstream of SOX9, encompassing the distal enhancer region. Integration with previously reported pathogenic copy-number variants allowed delineation of a shortest region of overlap within the upstream SOX9 regulatory landscape. Epigenomic annotation of this interval revealed open chromatin and enhancer-associated histone marks, together with strong vertebrate sequence conservation. Integration of single-cell datasets showed that this region corresponds to active enhancer signatures, supporting a role in testis-specific gene regulation.
Conclusions: Whole-genome sequencing identified deletions affecting a distal regulatory region upstream of SOX9 in individuals with 46,XY CGD. Integration of epigenomic resources refines the candidate cis-regulatory elements within this interval and supports the pathogenic role of non-coding variants disrupting SOX9 regulation. These findings highlight the importance of analyzing distal regulatory regions in the genetic diagnosis of DSD, particularly in patients with unexplained 46,XY CGD.
Volume 118
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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