Novel and Known DHX37 Variants in 46,XY DSD: Expanding the Genotypic and Phenotypic Spectrum.

Heterozygous missense variants in DHX37, an RNA helicase involved in testicular development, distributed across the RecA1 and RecA2 domains and the linker region proximal to the HA2 domain.

DHX37 variants are an established cause of 46,XY differences of sex development, but their spectrum remains incompletely defined. The authors retrospectively reviewed 108 patients with a 46,XY karyotype investigated by trio-based whole-exome sequencing at a single centre between January 2021 and December 2025, and analysed in detail six probands carrying a DHX37 variant with no other pathogenic or likely pathogenic variant in known genes. Phenotypes ranged from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia, with six heterozygous missense variants distributed across RecA1 (p.Arg334Trp), RecA2 (p.Val460Ala, p.Gly478Arg, p.Asp577Gly, p.Val652Ile) and the linker region proximal to the HA2 domain (p.Thr727Met). Under ACMG/AMP criteria only p.Arg334Trp was classified as pathogenic, the other five remaining variants of uncertain significance, and the authors state that the proposed genotype-phenotype correlations remain speculative in the absence of functional assays.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The real contribution is further confirmation of p.Arg334Trp and an expanded variant catalogue, not a step forward in interpretation: four of six novel variants return as variants of uncertain significance, leaving families without an answer usable in genetic counselling. Without functional assays, and with poorly informative segregation in a condition whose expression is limited to males, structural modelling is not enough to decide. File this among data to be aggregated, pending a multicentre cohort with functional characterisation.

Analysis by Dr Thibaut Benquey