SUN-176 - Identifying Genetic Variants Associated in Disorders of Sex Development using Genome Sequencing and AI-Driven Curation

Introduction: Disorders of Sex Development (DSD) comprise a heterogeneous group of congenital conditions characterized by a mismatch between chromosomal, gonadal, and anatomic sex. Achieving a definitive molecular diagnosis is critical for clinical management, including malignancy risk assessment, hormone replacement strategy, and genetic counseling. Despite the advent of targeted gene panels and exome sequencing, the molecular basis of DSDs is unclear for most patients. We completed Genome Sequencing (GS) coupled with advanced bioinformatic curation to identify clinically significant gene variants in a phenotypic DSD cohort.

Methods: We performed a retrospective genomic analysis of 11 patients with a clinical diagnosis of DSD. Four patients had diagnosis of 46,XX ovotesticular DSD, 4 patients were 46,XX males (2 SRY negative), and 3 patients were 46,XY with ambiguous genitalia. Genome sequencing was conducted to capture both coding and non-coding structural variations. Variant annotation, filtering, and prioritization were conducted using the Franklin by QIAGEN platform. Variants were curated based on the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) guidelines, focusing on phenotype and published DSD gene panels.

Results: Of the 11 patients analyzed, 8 had a pathogenic (P) and likely pathogenic (LP) variants and 5 (45%) of the patients exhibited variants that could potentially be associated with DSDs. One of the 46,XY DSD patients displayed biallelic variants in the HSD17B3 gene, while the second 46,XY DSD patient had biallelic variants in the HSD17B4 gene and the third had biallelic variants in the HSD17B4 gene and NRS5A1 gene. The 46,XX ovotesticular DSD patient displayed biallelic variants in both of the following genes: TBC1D32 and ASH1L. Another 46,XX ovotesticular DSD patient was found to have a variant in the VHL gene. Variants in two different genes could potentially be the result of digenicity or synergistic heterozygosity; however, this requires further investigation.

Conclusion: Our preliminary analysis showed that 5 out 11 patients displayed P/LP variants that could be potentially associated with DSDs. These findings are pending further confirmation.

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