Background: Differences of sex development (DSD) affect about 1% of live births and result from disruptions in chromosomal, gonadal, or genital development. Individuals with DSD often face long and inconclusive diagnostic journeys, underscoring the need for more effective genetic testing approaches. In particular, the diagnostic yield for 46,XY DSD, remains low around 50%. Whole-genome sequencing (WGS) enables the detection of both coding and non-coding variants, providing a more comprehensive view of the genome and improving the chance of identifying previously undetected pathogenic changes.
Aim: To identify novel genetic variants associated with 46,XY DSDs to improve the genetic diagnostic yield and provide better management options for affected individuals.
Methods: WGS was performed on seven individuals with 46,XY DSD to identify potential causative genes and variants. Patients were recruited from the National Children’s Hospital in Vietnam. Genomic DNA was extracted from peripheral blood samples, and WGS data were generated and processed using an in-house bioinformatics pipeline. The analysis included variant calling, annotation, and prioritization to identify rare or novel variants potentially associated with DSD.
Results: Among the seven 46,XY DSD cases, three novel variants were identified in known DSD genes: CYB5A, including one missense and one intronic variant; NR5A1, carrying an intronic variant; and KMT2D, with a novel missense variant. Additionally, previously reported pathogenic or likely pathogenic variants were detected, including one intronic variant in WT1 and two missense variants in SRD5A2.
Conclusion: Whole-genome sequencing enabled the identification of coding and non-coding variants in 46,XY DSD, allowing definitively genetic diagnosis for our seven patients.