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

To investigate the clinical characteristics, inheritance patterns, and genotype-phenotype correlations of DHX37 variants in 46,XY disorders of sex development (DSD).

We retrospectively reviewed 108 patients with 46,XY karyotype who underwent DSD evaluation and trio-based whole-exome sequencing (trio-WES) at our center between January 2021 and December 2025. Six probands with DHX37 variants and no concurrent pathogenic or likely pathogenic variants in other known DSD-associated genes were analyzed in detail. Clinical presentations, endocrine profiles, imaging findings, and pedigree data were collected. Variant segregation was confirmed by Sanger sequencing; variants were assessed using in silico prediction, conservation analysis, and structural modeling, and were classified according to ACMG/AMP guidelines.

The six probands exhibited marked phenotypic heterogeneity, with manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia. Six heterozygous DHX37 missense variants were identified across distinct functional domains: one in RecA1 [c.1000C>T (p.Arg334Trp)], four in RecA2 [c.1379T>C (p.Val460Ala), c.1432G>A (p.Gly478Arg), c.1730A>G (p.Asp577Gly), and c.1954G>A (p.Val652Ile)], and one in the linker region proximal to the HA2 domain [c.2180C>T (p.Thr727Met)]. Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg has been reported previously, albeit in the same patient included in the present study; and the remaining four were novel. According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining five as variants of uncertain significance.

This study provides additional case evidence supporting the pathogenicity of p.Arg334Trp and expands the DHX37 variant spectrum. Computational and structural analyses suggest that p.Gly478Arg may underlie the testicular regression syndrome phenotype of the corresponding proband and that the four novel variants may be involved in testicular development. However, these genotype-phenotype correlations remain speculative; larger cohorts and in vitro functional assays are warranted to confirm these associations.