Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.
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
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
09
02
2019
revised:
30
05
2019
accepted:
10
06
2019
pubmed:
18
6
2019
medline:
6
5
2020
entrez:
18
6
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31206972
doi: 10.1002/humu.23841
pmc: PMC6874899
mid: NIHMS1036426
doi:
Substances chimiques
Codon, Nonsense
0
Intracellular Signaling Peptides and Proteins
0
Nuclear Proteins
0
ZC4H2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2270-2285Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : Wellcome and the Department of Health, and the Wellcome Sanger Institute
ID : WT098051
Pays : International
Organisme : NHLBI NIH HHS
ID : X01HL132377
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States
Organisme : Department of Health
ID : RP-2016-07-011
Pays : United Kingdom
Organisme : Health Innovation Challenge Fund
ID : HICF-1009-003
Pays : International
Organisme : NEI NIH HHS
ID : R01EY027421
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY027421
Pays : United States
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek
ID : OND1312421
Pays : International
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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