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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 Kay 6 Matthieu Peycelon 7, 8, 9 Jean-Pierre Siffroi 7 Inas Mazen 10 John Achermann 5 Yuliya Shcherbak Juliane Leger 11 Agnes Sallai 12 Jean-Claude Carel 11 Laetitia Martinerie 11 Romain Le Ru 13, 14 Gerard Conway 15 Brigitte Mignot 13, 14 Lionel van Maldergem 13, 14 Rita Bertalan 12 Evgenia Globa Raja Brauner 16, 17 Ralf Jauch 4 Serge Nef 18 Andy Greenfield 6 Anu Bashamboo 1, *
* Corresponding author
1 Génétique du Développement humain - Human developmental genetics
2 Rigshospitalet [Copenhagen]
3 Génétique Evolutive Humaine - Human Evolutionary Genetics
4 HKU - The University of Hong Kong
5 UCL - University College of London [London]
6 MRC Harwell - Medical Research Coucil Harwell [Oxford, UK]
7 CHU Trousseau [APHP]
8 Hôpital Robert Debré Paris
9 IUPUI - Indiana University - Purdue University Indianapolis
10 National Research Centre [Cairo, Egypt]
11 Hôpital Robert Debré
12 Semmelweis University [Budapest]
13 UFC - Université de Franche-Comté
14 CHRU Besançon - Centre Hospitalier Régional Universitaire [Besançon]
15 Institute for Women's Health [London]
16 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
17 UPD5 - Université Paris Descartes - Paris 5
18 University of Geneva [Switzerland]
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.
Keywords : DHX37 RNA helicase disorders of sex development (DSD) ribosomopathy testicular regression syndrome
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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, Nature Publishing Group, In press, ⟨10.1038/s41436-019-0606-y⟩. ⟨pasteur-02376177⟩

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