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Mol Psychiatry. 2018 Feb;23(2):222-230. doi: 10.1038/mp.2016.135. Epub 2016 Aug 23.

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.

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GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, NSW, Australia.
School of Women and Children's Health, University of New South Wales, NSW, Australia.
Department Physiology and Pathology of Ion Transport, Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
Department Physiology and Pathology of Ion Transport, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
School of Medicine, The University of Adelaide, Adelaide, SA, Australia.
South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, SA, Australia.
Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Inserm U930 'Imaging and Brain', Tours, France.
University François-Rabelais, Tours, France.
Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
Department of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
Columbia University, New York, NY, USA.
Department of Pediatrics, San Antonio Military Medical Center, Fort Sam, Houston, TX, USA.
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO, USA.
West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, UK.
Department of Pediatrics, AMC University Hospital Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Genetics, AMC University Hospital Amsterdam, Amsterdam, The Netherlands.
Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA.
Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
SA Pathology, Women's and Children's Hospital, North Adelaide, SA, Australia.
Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.


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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