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

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita
Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita
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 9 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 9 carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, 4 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.
1059-7794
2270-2285
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Frints, Suzanna G.M., Henniges, Friederike, Colombo, Roberto, Jacquemont, Sebastien, Terhal, Paulien, Zimmermann, Holly, Hunt, David, Meldelson, Bryce A., Kordab, Ulrike, Webster, Richard, Sinnema, Margje, Abdul-Rahman, Omar, Suckow, Vanessa, Fernández-Jaén, Alberto, van Roozendaal, Kees, Stevens, Servi JC, Macville, Merryn VE, Al-Nasiry, Salwan, van Gassen, Koen L.I., Utzig, Norbert, Koudijs, Suzanne M., McGregor, Lesley, Maas, Saskia M., Baralle, Diana, Dixit, Abhijit, Wieacker, Peter, Lee, Marcus, Lee, Arthur S., Engle, Elizabeth C., Houge, Gunnar, Gradek, Gyri A., Douglas, Andrew, Longman, Cheryl, Joss, Shelagh, Velasco, Danita, Hennekam, Raoul C., Hirata, Hiromi and Kalscheuer, Vera M. (2019) Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. Human Mutation, 40 (12), 2270-2285. (doi:10.1002/humu.23841).

Record type: Article

Abstract

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 9 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 9 carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, 4 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.

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Frints_et_al-2019-Human_Mutation - Accepted Manuscript
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Accepted/In Press date: 10 June 2019
e-pub ahead of print date: 17 June 2019
Published date: 1 December 2019

Identifiers

Local EPrints ID: 432157
URI: http://eprints.soton.ac.uk/id/eprint/432157
ISSN: 1059-7794
PURE UUID: d34f2128-2b41-4df2-bbb2-5e13411eb5c1
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Andrew Douglas: ORCID iD orcid.org/0000-0001-5154-6714

Catalogue record

Date deposited: 03 Jul 2019 16:30
Last modified: 26 Nov 2021 02:55

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Contributors

Author: Suzanna G.M. Frints
Author: Friederike Henniges
Author: Roberto Colombo
Author: Sebastien Jacquemont
Author: Paulien Terhal
Author: Holly Zimmermann
Author: David Hunt
Author: Bryce A. Meldelson
Author: Ulrike Kordab
Author: Richard Webster
Author: Margje Sinnema
Author: Omar Abdul-Rahman
Author: Vanessa Suckow
Author: Alberto Fernández-Jaén
Author: Kees van Roozendaal
Author: Servi JC Stevens
Author: Merryn VE Macville
Author: Salwan Al-Nasiry
Author: Koen L.I. van Gassen
Author: Norbert Utzig
Author: Suzanne M. Koudijs
Author: Lesley McGregor
Author: Saskia M. Maas
Author: Diana Baralle ORCID iD
Author: Abhijit Dixit
Author: Peter Wieacker
Author: Marcus Lee
Author: Arthur S. Lee
Author: Elizabeth C. Engle
Author: Gunnar Houge
Author: Gyri A. Gradek
Author: Andrew Douglas ORCID iD
Author: Cheryl Longman
Author: Shelagh Joss
Author: Danita Velasco
Author: Raoul C. Hennekam
Author: Hiromi Hirata
Author: Vera M. Kalscheuer

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