ArticleAmerican journal of human genetics2013
ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.
- Pooled it
- Bradycardia, asystole, and sudden cardiac death inHeartRhythm case reports · 2026Article
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- Zinc-Induced Folding and Solution Structure of the Eponymous Novel Zinc Finger from the ZC4H2 Protein.Biomolecules · 2025Article
- The pathogenic factor of ZC4H2-associated rare disorder is a postsynaptic regulator for synaptic activity and cognitive function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Transcriptomic Profiling of Zebrafish Mutant forInternational journal of molecular sciences · 2025Article
- Identification and functional analysis of NPR2 truncating mutations in two Chinese families with short stature.BMC pediatrics · 2025Article
- Wieacker-Wolff syndrome with hyperinsulinemic hypoglycemia successfully treated using diazoxide: A case report.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Article
- Case Report: A novel missense variant inFrontiers in pediatrics · 2025Article
- Genotype-Phenotype Correlations and Sex Differences in ZC4H2-Associated Rare Disorder.Pediatric neurology · 2024Article
- Loss ofGenes · 2024Article
- A case of female-restricted Wieacker-Wolff syndrome with heart and endocrinological involvement.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy.Nature medicine · 2024Article
- Article
- Large-Scale Functional Assessment of Genes Involved in Rare Diseases with Intellectual Disabilities Unravels Unique Developmental and Behaviour Profiles in Mouse Models.Biomedicines · 2022Article
- A gain-of-function variant in the Wiskott-Aldrich syndrome gene is associated with a MYH9-related disease-like syndrome.Blood advances · 2022Article
- Article
- Need for revision of the ACMG/AMP guidelines for interpretation of X-linked variants.Intractable & rare diseases research · 2022Article
- Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.Journal of molecular cell biology · 2022Article
- Clinical findings and a DNA methylation signature in kindreds with alterations in ZNF711.European journal of human genetics : EJHG · 2022Article
Corrections and comments
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Authors and funding
44 authors at 18 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.
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