ArticleMolecular psychiatry2018
De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.
Article in Molecular psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 68 citations in OpenAlex.
- Abnormal ClC-3/TMEM9-mediated endosomal ion transport in CLCN3-associated neurodevelopmental disease.EMBO molecular medicine · 2026Article
- Expanding the Phenotypic Spectrum of Raynaud-Claes Syndrome: A Rett-like Presentation with Two New Cases.Genes · 2026Review
- Modeling rare coding variation on chromosome X provides insight into the genetics and differential sex prevalence of autism spectrum disorder.medRxiv : the preprint server for health sciences · 2026Article
- Cytogenetic, genomic, and reproductive characterization of four Pura Raza Española Mares carrying a 64, X, del(X), t(X; Y) complex karyotype.Journal of animal science · 2026Article
- Primary cilia as a molecular convergence hub linking neurodevelopment and autism spectrum disorder.Frontiers in cellular neuroscience · 2026Review
- Dominant Action ofCells · 2025Article
- Endosomal 2Cl-/H+ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density.Brain : a journal of neurology · 2025Article
- Comorbidity of Attention Deficit Hyperactivity Disorder (ADHD) and Chung-Jansen Syndrome: Case Report and Review of Literature.Clinical case reports · 2025Article
- Disruption of ClC-3-mediated 2ClScientific reports · 2025Article
- Clinical features and genetic analysis of epilepsy caused byTranslational pediatrics · 2025Article
- Endosomal chloride/proton exchangers need inhibitory TMEM9 β-subunits for regulation and prevention of disease-causing overactivity.Nature communications · 2025Article
- Developmental deficits, synapse and dendritic abnormalities in a Clcn4 KO autism mice model: endophenotypic target for ASD.Translational psychiatry · 2025Article
- Role of voltage-gated chloride channels in epilepsy: current insights and future directions.Frontiers in pharmacology · 2025Review
- TMEM9B Regulates Endosomal ClC-3 and ClC-4 Transporters.Life (Basel, Switzerland) · 2024Article
- Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.Nature communications · 2024Article
- Expanding the genetic and phenotypic relevance of CLCN4 variants in neurodevelopmental condition: 13 new patients.Journal of neurology · 2024Article
- Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.Human genetics · 2024Article
- Biophysical and Pharmacological Insights to CLC Chloride Channels.Handbook of experimental pharmacology · 2024Article
- Experience with the Ketogenic Diet in a Boy withBalkan journal of medical genetics : BJMG · 2023Article
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Authors and funding
50 authors at 20 institutions in 7 countries.
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Abstract
Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.
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