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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

Ken Mcelreavey 1 Anne Jørgensen 2 Caroline Eozenou 1 Tiphanie Merel 1 Joelle Bignon-Topalovic 3 Daisylyn Senna Tan 4 Denis Houzelstein 3 Federica Buonocore 5 Nick Warr 6 Raissa G G Kay 6 Matthieu Peycelon 7, 8, 9 Jean-Pierre Siffroi 7, 10, 11 Inas Mazen 12 John C Achermann 5 Yuliya Shcherbak Juliane Leger 13 Agnes Sallai 14 Jean-Claude Carel 13 Laetitia Martinerie 13 Romain Le Ru 15, 16 Gerard Conway 17 Brigitte Mignot 15, 16 Lionel van Maldergem 15, 16 Rita Bertalan 14 Evgenia Globa Raja Brauner 18, 19 Ralf Jauch 4 Serge Nef 20 Andy Greenfield 6 Anu Bashamboo 1, * 
Abstract : 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.
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Ken Mcelreavey, Anne Jørgensen, Caroline Eozenou, Tiphanie Merel, Joelle Bignon-Topalovic, et al.. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome. Genetics in Medicine, 2020, 22 (1), pp.150-159. ⟨10.1038/s41436-019-0606-y⟩. ⟨pasteur-02376177⟩

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