A novel DEAH-box helicase 37 mutation associated with differences of sex development.

OBJECTIVE

To determine the genetic etiology of a family pedigree with two patients affected by differences of sex development (DSD).

METHODS

Assess the clinical characteristics of the patients and achieve exome sequencing results and functional studies.

RESULTS

The 15-year-old proband, raised as female, presented with delayed puberty and short stature associated with atypical genitalia. Hormonal profile showed hypergonadotrophic hypogonadism. Imaging studies revealed the absence of a uterus and ovaries. The karyotype confirmed a 46, XY pattern. Her younger brother presented with a micropenis and hypoplastic scrotum with non-palpable testis and hypospadias. Laparoscopic exploration was performed on the younger brother. Streak gonads were found and removed due to the risk of neoplastic transformation. Post-operative histopathology showed the co-existence of Wolffian and Müllerian derivatives. Whole-exome sequencing identified a novel mutation (c.1223C>T, p. Ser408Leu) in the Asp-Glu-Ala-His-box helicase 37 gene, which was found to be deleterious by analysis. Segregation analysis of the variant displayed a sex-limited, autosomal dominant, maternal inheritance pattern. experiments revealed that the substitution of 408Ser by Leu caused decreased DHX37 expression both at the mRNA and protein levels. Moreover, the β-catenin protein was upregulated, and the p53 protein was unaltered by mutant .

CONCLUSIONS

We described a novel mutation (c.1223C>T, p. Ser408Leu) of the gene associated with a Chinese pedigree consisting of two 46, XY DSD patients. We speculated that the underlying molecular mechanism might involve upregulation of the β-catenin protein.