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

TitlePathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome
Authors
KeywordsDHX37
disorders of sex development (DSD)
ribosomopathy
RNA helicase
testicular regression syndrome
Issue Date2019
PublisherSpringer Nature for American College of Medical Genetics. The Journal's web site is located at http://www.nature.com/gim/index.html
Citation
Genetics In Medicine, 2019 How to Cite?
AbstractPurpose: 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.
Persistent Identifierhttp://hdl.handle.net/10722/272729
ISSN
2019 Impact Factor: 8.904
2015 SCImago Journal Rankings: 3.545

 

DC FieldValueLanguage
dc.contributor.authorMcElreavey, K-
dc.contributor.authorJorgensen, A-
dc.contributor.authorEozenou, C-
dc.contributor.authorMerel, T-
dc.contributor.authorBignon-Topalovic, J-
dc.contributor.authorTan, DS-
dc.contributor.authorHouzelstein, D-
dc.contributor.authorBuonocore, F-
dc.contributor.authorWarr, N-
dc.contributor.authorKay, RGG-
dc.contributor.authorPeycelon, M-
dc.contributor.authorSiffroi, J-P-
dc.contributor.authorMazen, I-
dc.contributor.authorAchermann, JC-
dc.contributor.authorShcherbak, Y-
dc.contributor.authorLeger, J-
dc.contributor.authorSallai, A-
dc.contributor.authorCarel, J-C-
dc.contributor.authorMartinerie, L-
dc.contributor.authorLe Ru, R-
dc.contributor.authorConway, GS-
dc.contributor.authorMignot, B-
dc.contributor.authorMaldergem, LV-
dc.contributor.authorBertalan, R-
dc.contributor.authorGloba, E-
dc.contributor.authorBrauner, R-
dc.contributor.authorJauch, R-
dc.contributor.authorNef, S-
dc.contributor.authorGreenfield, A-
dc.contributor.authorBashamboo, A-
dc.date.accessioned2019-08-06T09:15:27Z-
dc.date.available2019-08-06T09:15:27Z-
dc.date.issued2019-
dc.identifier.citationGenetics In Medicine, 2019-
dc.identifier.issn1098-3600-
dc.identifier.urihttp://hdl.handle.net/10722/272729-
dc.description.abstractPurpose: 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.-
dc.languageeng-
dc.publisherSpringer Nature for American College of Medical Genetics. The Journal's web site is located at http://www.nature.com/gim/index.html-
dc.relation.ispartofGenetics In Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectDHX37-
dc.subjectdisorders of sex development (DSD)-
dc.subjectribosomopathy-
dc.subjectRNA helicase-
dc.subjecttesticular regression syndrome-
dc.titlePathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome-
dc.typeArticle-
dc.identifier.emailJauch, R: ralf@hku.hk-
dc.identifier.authorityJauch, R=rp02383-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41436-019-0606-y-
dc.identifier.pmid31337883-
dc.identifier.scopuseid_2-s2.0-85069497061-
dc.identifier.hkuros300402-
dc.publisher.placeUnited States-

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