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Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

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  • Ken McElreavey
  • Anne Jorgensen
  • Caroline Eozenou
  • Tiphanie Merel
  • Joelle Bignon-Topalovic
  • Daisylyn Senna Tan
  • Denis Houzelstein
  • Federica Buonocore
  • Nick Warr
  • Raissa G G Kay
  • Matthieu Peycelon
  • Jean-Pierre Siffroi
  • Inas Mazen
  • John C Achermann
  • Yuliya Shcherbak
  • Juliane Leger
  • Agnes Sallai
  • Jean-Claude Carel
  • Laetitia Martinerie
  • Romain Le Ru
  • Gerard S Conway
  • Brigitte Mignot
  • Lionel Van Maldergem
  • Rita Bertalan
  • Evgenia Globa
  • Raja Brauner
  • Ralf Jauch
  • Serge Nef
  • Andy Greenfield
  • Anu Bashamboo
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PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown.

METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS.

RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis.

CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including 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.

Original languageEnglish
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number1
Pages (from-to)150-159
Number of pages10
Publication statusPublished - Jan 2020

    Research areas

  • DHX37, disorders of sex development (DSD), ribosomopathy, RNA helicase, testicular regression syndrome

ID: 57679298