XY individuals with Disorders/Differences of Sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or, more rarely, testis regression during early fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. Identification of novel genes involved in DSD is crucial for providing an accurate clinical diagnosis, aiding patient management and understanding the biological processes involved. We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology gonadal dysgenesis (n=81), TRS (n=16), boys with penoscrotal hypospadias (n=33) or anorchia (n=15). Thirteen children carried heterozygous missense mutations involving the RNA helicase DHX37, which is essential for ribosome biogenesis in yeast. Enrichment of rare/novel DHX37 missense mutations in 46,XY DSD is highly significant compared to controls (P value = 5.8x10-10). Five mutations are de novo (P value = 1.5x10-5). Twelve mutations are grouped in two highly conserved functional domains and are predicted to disrupt biological function. Mutations were specifically associated with gonadal dysgenesis (9/81, 11%) and TRS (4/16, 25%). Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. DHX37 mutations are a relatively common cause of an autosomal dominant form of 46,XY DSD, which includes both gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology