Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

Suzanna G.M. Frints, Friederike Hennig, Roberto Colombo, Sebastien Jacquemont, Paulien Terhal, Holly H. Zimmerman, David Hunt, Bryce A. Mendelsohn, Ulrike Kordaß, Richard Webster, Margje Sinnema, Omar Abdul-Rahman, Vanessa Suckow, Alberto Fernández-Jaén, Kees van Roozendaal, Servi J.C. Stevens, Merryn V.E. Macville, Salwan Al-Nasiry, Koen van Gassen, Norbert UtzigSuzanne M. Koudijs, Lesley McGregor, Saskia M. Maas, Diana Baralle, Abhijit Dixit, Peter Wieacker, Marcus Lee, Arthur S. Lee, Elizabeth C. Engle, Gunnar Houge, Gyri A. Gradek, Andrew G.L. Douglas, Cheryl Longman, Shelagh Joss, Danita Velasco, Raoul C. Hennekam, Hiromi Hirata, Vera M. Kalscheuer

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

Original languageEnglish (US)
Pages (from-to)2270-2285
Number of pages16
JournalHuman mutation
Issue number12
StatePublished - Dec 1 2019


  • Xq11.2 microdeletion
  • ZC4H2
  • ZC4H2-Associated Rare Disorders (ZARD)
  • club foot/-feet
  • complicated spastic paraplegia/ spasticity
  • fetal hypo-/akinesia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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