High Molecular Diagnosis Rate in Undermasculinized Males with Differences in Sex Development Using a Stepwise...

Area of Science:

• Genetics and genomics
• Endocrinology
• Pediatric medicine

Background:

• Differences of Sex Development (DSDs) encompass conditions with atypical sexual development, often requiring genetic identification for management.
• Current molecular diagnostic rates for undermasculinized males are below 50%, limiting effective clinical intervention.
• Next-generation sequencing (NGS) shows promise for improving DSD diagnostics, but its efficacy in larger cohorts is unestablished.

Purpose of the Study:

• To implement and evaluate a tiered genetic testing strategy in undermasculinized males within an interdisciplinary DSD clinic.
• To enhance the molecular diagnosis rate for DSD patients using a stepwise genetic analysis approach.
• To assess the diagnostic yield of whole-exome sequencing (WES) compared to other genetic tests in this cohort.

Main Methods:

• A cohort of 60 undermasculinized males (2008-2016) underwent a tiered genetic testing protocol.
• Testing progressed from karyotype and single-gene analysis to microarray, gene panels, and finally WES if prior tests were inconclusive.
• Deletion/duplication studies were performed when deletions were suspected.

Main Results:

• An overall molecular diagnosis rate of 62% (37/60) was achieved in patients with Y chromosomes.
• For 46,XY individuals, the overall diagnosis rate was 46%.
• Among 46,XY patients who completed all tiered testing, including WES, the diagnosis rate reached 64% (18/28).

Conclusions:

• A tiered genetic testing approach significantly increases molecular diagnostic yield in undermasculinized males with DSDs.
• Whole-exome sequencing (WES) is a valuable tool, demonstrating higher diagnostic capability than gene panel testing alone.
• Improved genetic diagnoses facilitate better clinical management and understanding of DSDs.