Refining the diagnosis of 46,XY disorders of sex development: insight from whole-exome sequencing

Whole-exome sequencing in deeply phenotyped 46,XY DSD patients

Whole-exome sequencing was performed in 39 deeply phenotyped 46,XY DSD children. A genetic cause explaining the phenotype was identified in 8 children, with pathogenic or likely pathogenic variants in AR, DHX37, and HSD17B3, and VUS in NR5A1, DHX37, AR, MAMLD1, SOS2, and FAM111A. The most common etiology was androgen insensitivity syndrome. Pathogenic variants in genes unrelated to DSD were identified in 7 patients. The authors observed frequent genotype-phenotype discordance and recommend exome re-analysis at 12-24 months in the absence of a diagnosis.

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The study confirms a frustrating reality of 46,XY DSD: even broad WES leaves about half of cases without a molecular diagnosis in well-phenotyped patients. Genotype-phenotype discordance and the discovery of variants in non-DSD genes argue for exome/genome analysis with periodic re-interrogation rather than a fixed panel. An honest descriptive study whose main value is methodological (deferred re-analysis).