Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.
Details
Serval ID
serval:BIB_753B7D2B2637
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.
Journal
Human mutation
ISSN
1098-1004 (Electronic)
ISSN-L
1059-7794
Publication state
Published
Issued date
12/2019
Peer-reviewed
Oui
Volume
40
Number
12
Pages
2270-2285
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
Keywords
Animals, Arthrogryposis/genetics, Codon, Nonsense, Disease Models, Animal, Female, Frameshift Mutation, Genes, X-Linked, Genetic Predisposition to Disease, Humans, Intracellular Signaling Peptides and Proteins/genetics, Male, Mutation, Mutation, Missense, Nuclear Proteins/genetics, Pedigree, Phenotype, Sequence Deletion, Sex Characteristics, Zebrafish, Xq11.2 microdeletion, ZC4H2, ZC4H2-Associated Rare Disorders (ZARD), club foot/-feet, complicated spastic paraplegia/ spasticity, fetal hypo-/akinesia
Pubmed
Web of science
Create date
24/06/2019 17:56
Last modification date
20/06/2020 6:18