Genetic Testing Strategy Effectively Pinpoints Definitive Molecular Diagnosis, Suggests Study

Due to the highly heterogeneous nature of DSD and the critical clinical gap in obtaining precise molecular diagnoses to effectively guide personalized patient management over time, Dr. Vandana Jain and collaborative colleagues of a tertiary hospital in India aimed to comprehensively assess clinical characteristics and perform targeted molecular profiling in a notably large Indian pediatric cohort.

Therefore, the comprehensive observational study enrolled 147 children, presenting with a median age of 3.8 years, from a dedicated tertiary care setting to undergo meticulous longitudinal clinical data collection and stepwise genetic testing; the analytical methods included targeted Sanger sequencing for specific suspected genes, subsequently followed by a broad 155-gene Next-Generation Sequencing (NGS) panel to thoroughly evaluate the remaining undiagnosed patients.

Key Clinical Findings of the Study Includes:

• Provisional Assessments: Investigators noted that based on initial clinical, biochemical, and radiological evaluations, 56.5% of cases were provisionally suspected to have 5α-reductase type 2 (5αR2) deficiency or androgen insensitivity syndrome (AIS), while 21% presented with gonadal dysgenesis and 7.5% demonstrated a testosterone biosynthetic defect.

• Targeted Screening Success: Researchers found that sequential single-gene testing successfully identified pathogenic or likely pathogenic variants in 44 out of 75 evaluated subjects who initially had a strong clinical suspicion of 5αR2 deficiency or AIS.

• Advanced Sequencing Yield: Scientists reported that utilizing the comprehensive 155-gene NGS panel on the remaining 103 children successfully uncovered pathogenic or likely pathogenic mutations in 20 additional subjects, distributed across 12 distinct genetic markers.

• Primary Genetic Drivers: Authors highlighted that the NR5A1 gene notably emerged as the most frequently implicated genetic factor in the NGS-tested cohort, affecting 7 out of 103 cases, which perfectly complemented the high prevalence of SRD5A2 and AR gene variants.

• Cumulative Diagnostic Rate: Clinicians concluded that the combined step-by-step methodological approach ultimately achieved a definitive molecular confirmation for 68 out of the 147 enrolled children, representing a substantial 46% overall success rate for the cohort.

The results suggest that deploying targeted Sanger sequencing followed by comprehensive NGS is a highly effective diagnostic pathway, ultimately resolving the molecular etiology for nearly half (46%) of this large Indian DSD cohort.

Securing a precise molecular diagnosis can gently assist healthcare providers in tailoring long-term management by offering clearer insights into the underlying pathophysiology of sex development, future reproductive potential, and associated risks for tumor formation or extragenital complications.

While the sequential testing strategy proved robust for a significant portion of the cohort, it may be beneficial for future research to gently explore the remaining uncharacterized genetic profiles to further illuminate the diagnostic landscape for all patients.

Reference

Jain, V., Priyadarshini, S., Sharma, R., Kumar, A., Sharma, S., Raghupathy, P., Werner, R., Hiort, O., & Faruq, M. (2026). Clinical Characterization and Molecular Profiling by Targeted Next-Generation Sequencing in a Large Indian Cohort With 46,XY Differences in Sex Development. Clinical Endocrinology.

Suggested Titles for the News Article:

• Stepwise Genetic Testing Resolves 46% of 46,XY DSD Cases

• Molecular Profiling Enhances Diagnostic Yield in Pediatric DSD

• Targeted Sequencing Guides Clinical Management in DSD Patients

• Unlocking Genetic Etiologies: A New Era for 46,XY DSD Diagnosis