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

Frints, S. G. M., Hennig, F., Colombo, R., Jacquemont, S., Terhal, P., Zimmerman, H. H., et al. (2019). Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. Human Mutation, 2019, 1-16. doi:10.1002/humu.23841.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-AC66-8 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-AC67-7
Genre: Journal Article

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 Creators:
Frints, Suzanna G. M. , Author
Hennig, Friederike1, Author              
Colombo, Roberto , Author
Jacquemont, Sebastien , Author
Terhal, Paulien , Author
Zimmerman, Holly H. , Author
Hunt, David, Author
Mendelsohn, Bryce A. , Author
Kordaß, Ulrike, Author
Webster, Richard , Author
Sinnema, Margje , Author
Abdul‐Rahman, Omar , Author
Suckow, Vanessa1, Author              
Fernández‐Jaén, Alberto , Author
van Roozendaal, Kees , Author
Stevens, Servi J. C. , Author
Macville, Merryn V. E. , Author
Al‐Nasiry, Salwan , Author
van Gassen, Koen , Author
Utzig, Norbert , Author
Koudijs, Suzanne M., AuthorMcGregor, Lesley , AuthorMaas, Saskia M. , AuthorBaralle, Diana , AuthorDixit, Abhijit , AuthorWieacker, Peter , AuthorLee, Marcus , AuthorLee, Arthur S. , AuthorEngle, Elizabeth C. , AuthorHouge, Gunnar , AuthorVelasco, Danita , AuthorHennekam, Raoul C. , AuthorHirata, Hiromi , AuthorKalscheuer, Vera M.1, Author               more..
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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

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Language(s): eng - English
 Dates: 2019-06-102019-06-17
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/humu.23841
PMID: 31206972
 Degree: -

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Title: Human Mutation
  Other : Hum Mut
Source Genre: Journal
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Publ. Info: New York, N.Y. : Wiley-Liss
Pages: - Volume / Issue: 2019 Sequence Number: - Start / End Page: 1 - 16 Identifier: ISSN: 1059-7794 (print)
ISSN: 1098-1004 (online)
CoNE: https://pure.mpg.de/cone/journals/resource/954925597586