title: 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.
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.
authors.affiliation: 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.
authors.forename: E E
authors.initials: EE
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Stuhlmann
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Weinert
authors.affiliation: 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.
authors.forename: E
authors.initials: E
authors.lastname: Haan
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Holvoet
authors.affiliation: GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, NSW, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Boyle
authors.affiliation: GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Leffler
authors.affiliation: Inserm U930 'Imaging and Brain', Tours, France.|University François-Rabelais, Tours, France.|Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Raynaud
authors.affiliation: Inserm U930 'Imaging and Brain', Tours, France.|University François-Rabelais, Tours, France.|Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Moraine
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.
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authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: K
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: H-H
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Delgado
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sirsi
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Golla
authors.affiliation: Department of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Department of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Pietryga
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wynn
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Rohena
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bernardo
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hamlin
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam, Houston, TX, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Faux
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO, USA.
authors.forename: L
authors.initials: L
authors.lastname: Manwaring
authors.affiliation: West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, UK.
authors.forename: J
authors.initials: J
authors.lastname: Tolmie
authors.affiliation: West of Scotland Clinical Genetics Service, Southern General Hospital, Glasgow, UK.
authors.forename: S
authors.initials: S
authors.lastname: Joss
authors.affiliation: Department of Pediatrics, AMC University Hospital Amsterdam, Amsterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Cobben
authors.affiliation: Department of Clinical Genetics, AMC University Hospital Amsterdam, Amsterdam, The Netherlands.
authors.forename: F A M
authors.initials: FAM
authors.lastname: Duijkers
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Goehringer
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Challman
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Hennig
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Grimme
authors.affiliation: Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Suckow
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Musante
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, SA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Nicholl
authors.affiliation: School of Medicine, The University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Shaw
authors.affiliation: School of Women and Children's Health, University of New South Wales, NSW, Australia.
authors.forename: S P
authors.initials: SP
authors.lastname: Lodh
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: 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.
authors.forename: T J
authors.initials: TJ
authors.lastname: Jentsch
authors.affiliation: School of Medicine, The University of Adelaide, Adelaide, SA, Australia.|Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Gecz
authors.affiliation: GOLD (Genetics of Learning and Disability) Service, Hunter Genetics, Waratah, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Field
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: V M
authors.initials: VM
authors.lastname: Kalscheuer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics; D000073376:Epileptic Syndromes / Q000235:genetics* / Q000503:physiopathology; D005190:Family; D005260:Female; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009865:Oocytes; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D066127:White Matter / Q000503:physiopathology; D014982:Xenopus laevis
chemical_list: C484312:CLCN4 protein, human; D018118:Chloride Channels