Clinical Characterization and Molecular Profiling by Targeted Next-Generation Sequencing in a Large Indian Cohort...

Area of Science:

• Genetics
• Endocrinology
• Pediatrics

Background:

• 46,XY differences in sex development (DSD) represent a diverse group of conditions.
• Accurate molecular diagnosis is crucial for guiding patient management, understanding pathophysiology, and assessing risks for tumors and extragenital issues.

Purpose of the Study:

• To determine the yield of molecular diagnosis in Indian children with 46,XY DSD using a stepwise genetic testing approach.
• To identify the most commonly implicated genes in this cohort.

Main Methods:

• Comprehensive clinical, biochemical, and radiological assessments were performed on 147 children with 46,XY DSD.
• Stepwise genetic testing included targeted sequencing of SRD5A2 and AR, followed by next-generation sequencing (NGS) of a 155-gene panel for remaining cases.
• Longitudinal clinical data was collected.

Main Results:

• A molecular diagnosis was achieved in 46% (68/147) of the cohort.
• Pathogenic variants in SRD5A2 and AR were identified in 44/75 patients with suspected 5α-reductase type 2 deficiency/androgen insensitivity syndrome (AIS).
• NGS identified variants in 20/103 children across 12 genes, with NR5A1 being the most frequent (7%).

Conclusions:

• A combined approach of Sanger sequencing and NGS enabled molecular diagnosis in 46% of this Indian cohort with 46,XY DSD.
• SRD5A2, AR, and NR5A1 were the most frequently implicated genes in the studied population.