Genetic evidence of the association of DEAH-box helicase 37 defects with 46,XY gonadal dysgenesis spectrum.

CONTEXT: 46,XY gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS).

OBJECTIVE: To report a novel gene for 46,XY GD etiology, especially for ETRS.

DESIGN: Screening of familial cases of 46,XY GD using WES and sporadic cases by target gene panel sequencing.

SETTING: Tertiary referral center for Differences/Disorders of sex Development (DSD).

PATIENTS AND METHODS: We selected 87 patients with 46,XY DSD (17 familial cases from eight unrelated families and 70 sporadic cases); 55 patients had GD (among them, ten patients from five families and eight sporadic cases had ETRS) and 32 patients had 46,XY DSD of unknown etiology.

RESULTS: We identified four heterozygous missense rare variants classified as pathogenic or likely pathogenic in DEAH-box helicase 37 (DHX37) gene in five families (n=11 patients) and in six sporadic cases. Two variants were recurrent: the p.Arg308Gln (in two families and in three sporadic cases) and the p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted to be deleterious DHX37 variants in this cohort (0.14) is significantly higher than that observed in gnomAD database (0.004; p<0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells, at different stages of testis maturation, in Leydig cells and rarely in Sertoli cells.

CONCLUSION: This strong genetic evidence identifies DHX37 as a new player in the complex cascade of male gonadal differentiation and maintenance.