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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| Affiliation: | 1. Human Developmental Genetics Unit, Institut Pasteur, Paris, France;2. Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark;3. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;4. Genetics and Genomic Medicine, UCL GOS Institute of Child Health, UCL, London, UK;5. Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire, UK;6. AP-HP, Hôpital d’Enfants Armand-Trousseau, Genetics and Embryology Department; Sorbonne Université; INSERM UMRS_933, Paris, France;7. 7AP-HP, Hôpital Universitaire Robert-Debré, Pediatric Urology Department,; Reference Center for Rare Diseases (CRMR) Malformations Rares des Voies Urinaires (MARVU), Université de Paris, Paris, France;8. Riley Children Hospital, Pediatric Urology Department; Indiana University, School of Medicine, Indianapolis, USA;;9. Genetics Department, National Research Center, Cairo, Egypt;10. National Hospital, OHMATDYT, Kyiv, Ukraine;11. Endocrinology et Diabetic Pediatrics, Hospital Robert Debre, Paris, France;12. Second Department of Paediatrics, Semmelweis University, Budapest, Hungary;13. Department of Pathology, University Hospital, University of Franche-Comté, Besançon, France;;14. Reproductive Medicine Unit, Institute for Women’s Health UCL, London, UK;15. Department of Pediatrics, University Hospital, University of Franche-Comté, Besançon, France;;16. Human Genetics Center, University Hospital, University of Franche-Comté, Besançon, France;17. First Department of Paediatrics, Semmelweis University, Budapest, Hungary;18. Ukrainian Center of Endocrine Surgery Endocrine Organs and Tissue Transplantation, MoH of Ukraine, Kyiv, Ukraine;19. Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, Paris, France;20. Department of Genetic Medicine and Development University of Geneva, Geneva, Switzerland;1. Human Developmental Genetics Unit, Institut Pasteur, Paris, France;2. Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark;3. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;4. Genetics and Genomic Medicine, UCL GOS Institute of Child Health, UCL, London, UK;5. Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire, UK;6. AP-HP, Hôpital d’Enfants Armand-Trousseau, Genetics and Embryology Department; Sorbonne Université; INSERM UMRS_933, Paris, France;7. 7AP-HP, Hôpital Universitaire Robert-Debré, Pediatric Urology Department,; Reference Center for Rare Diseases (CRMR) Malformations Rares des Voies Urinaires (MARVU), Université de Paris, Paris, France;8. Riley Children Hospital, Pediatric Urology Department; Indiana University, School of Medicine, Indianapolis, USA;;9. Genetics Department, National Research Center, Cairo, Egypt;10. National Hospital, OHMATDYT, Kyiv, Ukraine;11. Endocrinology et Diabetic Pediatrics, Hospital Robert Debre, Paris, France;12. Second Department of Paediatrics, Semmelweis University, Budapest, Hungary;13. Department of Pathology, University Hospital, University of Franche-Comté, Besançon, France;;14. Reproductive Medicine Unit, Institute for Women’s Health UCL, London, UK;15. Department of Pediatrics, University Hospital, University of Franche-Comté, Besançon, France;;16. Human Genetics Center, University Hospital, University of Franche-Comté, Besançon, France;17. First Department of Paediatrics, Semmelweis University, Budapest, Hungary;18. Ukrainian Center of Endocrine Surgery Endocrine Organs and Tissue Transplantation, MoH of Ukraine, Kyiv, Ukraine;19. Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, Paris, France;20. Department of Genetic Medicine and Development University of Geneva, Geneva, Switzerland |
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| Abstract: | PurposeXY 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.MethodsWe performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS.ResultsThirteen 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.ConclusionDHX37 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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