ArticleMolecular psychiatry2023
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
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Article in Molecular psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23citing papers in PubMed
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23 citing papers in PubMed, 33 citations in OpenAlex.
- An All-Optical Approach to Probe Chloride Transport with a Bright ChlorON.bioRxiv : the preprint server for biology · 2026Article
- 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
- Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.Scientific reports · 2026Article
- Dominant Action ofCells · 2025Article
- Endosomal 2Cl-/H+ exchangers regulate neuronal excitability by tuning Kv7/KCNQ channel density.Brain : a journal of neurology · 2025Article
- Structural basis of ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)PNature structural & molecular biology · 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
- 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
- Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.Journal of neurology · 2024Review
- Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.Human genetics · 2024Article
- Structural basis of pH-dependent activation in a CLC transporter.Nature structural & molecular biology · 2024Article
- Article
- Experience with the Ketogenic Diet in a Boy withBalkan journal of medical genetics : BJMG · 2023Article
- CryoEM structures of the human CLC-2 voltage gated chloride channel reveal a ball and chain gating mechanism.bioRxiv : the preprint server for biology · 2023Article
- Molecular basis of ClC-6 function and its impairment in human disease.Science advances · 2023Article
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Authors and funding
99 authors at 20 institutions in 14 countries.
Elizabeth E Palmer *Centre for Clinical Genetics, Sydney Children's Hospital Network, Randwick, NSW, Australia. elizabeth.palmer@unsw.edu.au.ORCID 0000-0003-1844-215X
Michael Pusch *Istituto di Biofisica, CNR, Genova, Italy. michael.pusch@ibf.cnr.it.ORCID 0000-0002-8644-8847
Alessandra PicolloIstituto di Biofisica, CNR, Genova, Italy.
Caitlin ForwoodCentre for Clinical Genetics, Sydney Children's Hospital Network, Randwick, NSW, Australia.
Matthew H NguyenDiscipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Randwick, NSW, Australia.
Vanessa SuckowMax Planck Institute for Molecular Genetics, Group Development and Disease, Berlin, Germany.
Jessica GibbonsMax Planck Institute for Molecular Genetics, Group Development and Disease, Berlin, Germany.
Alva HoffIstituto di Biofisica, CNR, Genova, Italy.
Lisa SigfridIstituto di Biofisica, CNR, Genova, Italy.
Andre MegarbaneDepartment of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
Mathilde NizonService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France.
Benjamin CognéService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France.
Claire BeneteauService de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France.ORCID 0000-0002-1682-523X
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.ORCID 0000-0003-4158-341X
Aziza ChedrawiDepartment of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Mais O HashemDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Hannah StambergerApplied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Sarah WeckhuysenApplied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Arnaud VanlanderDepartment of Child Neurology & Metabolism, Ghent University Hospital, Ghent, Belgium.
Berten CeulemansDepartment of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Sulekha RajagopalanDepartment of Clinical Genetics, Liverpool Hospital, Liverpool, NSW, Australia.
Kenneth NunnChildren's Hospital at Westmead, Sydney Children's Hospitals Network, Sydney, Australia.
Stéphanie ArpinService de Génétique Clinique, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
Martine RaynaudService de Génétique Clinique, Centre Hospitalier Régional Universitaire de Tours, Tours, France.
Constance S MotterGenetic Center, Akron Children's Hospital, Akron, OH, USA.
Catherine Ward-MelverGenetic Center, Akron Children's Hospital, Akron, OH, USA.
Katrien JanssensCenter of Medical Genetics, University Hospital Antwerp/University of Antwerp, Edegem, Belgium.
Marije MeuwissenCenter of Medical Genetics, University Hospital Antwerp/University of Antwerp, Edegem, Belgium.
Diane BeysenDepartment of Pediatric Neurology, University Hospital Antwerp/University of Antwerp, Edegem, Belgium.
Nicola DikowInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Mona GrimmelInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Emma ClementDepartment of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
Amy McTagueDevelopmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, UK.ORCID 0000-0002-0334-2909
David HuntWessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Sharron TownshendGenetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia.
Michelle WardGenetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia.
Linda J RichardsDepartment of Neuroscience, Washington University in St Louis School of Medicine, St Louis, MI, USA.
Cas SimonsCentre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia.
Gregory CostainDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
Lucie DupuisDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.ORCID 0000-0002-6068-8199
Roberto Mendoza-LondonoDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
Tracy Dudding-BythGenetics of Learning Disability Service, Newcastle, NSW, Australia.
Jackie BoyleGenetics of Learning Disability Service, Newcastle, NSW, Australia.
Carol SaundersDepartment of Pathology and Laboratory Medicine, Children's Mercy Hospital and Clinics, MI, Kansas City, USA.
Emily FlemingDivision of Clinical Genetics, Children's Mercy Hospital and Clinics, Kansas City, MI, USA.
Salima El ChehadehService de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID 0000-0003-1613-6570
Marie-Aude SpitzService de Pédiatrie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Amelie PitonLaboratoires de Diagnostic Génétique, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.
Bénédicte GerardLaboratoires de Diagnostic Génétique, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.
Marie-Thérèse Abi WardeService de Pédiatrie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Gillian ReaNorthern Ireland Regional Genetics Service, Belfast, Northern Ireland.
Caoimhe McKennaNorthern Ireland Regional Genetics Service, Belfast, Northern Ireland.
Sofia DouzgouDepartment of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID 0000-0002-8527-2210
Cigdem AkmanDepartment of Neurology, Division of Child Neurology, Columbia University Irving Medical Center, New York, USA.
Jennifer M BainDepartment of Neurology, Division of Child Neurology, Columbia University Irving Medical Center, New York, USA.ORCID 0000-0002-6642-8902
Tristan T SandsDepartment of Neurology, Division of Child Neurology, Columbia University Irving Medical Center, New York, USA.ORCID 0000-0001-7285-1195
Golder N WilsonTexas Tech Health Sciences Center Lubbock and KinderGenome Medical Genetics, Dallas, TX, USA.
Erin J SilvertoothTexas Sports Psychiatry and Integrative Health, Austin, TX, USA.
Lauren MillerHillcrest Internal Medicine, Waco, TX, USA.
Damien LedererCentre de Génétique Humaine, Institut de Pathologie et de Génétique ASBL, Gosselies, Belgium.
Rani SachdevCentre for Clinical Genetics, Sydney Children's Hospital Network, Randwick, NSW, Australia.
Rebecca MacintoshCentre for Clinical Genetics, Sydney Children's Hospital Network, Randwick, NSW, Australia.
Olivier MonestierCentre de Génétique Humaine, Institut de Pathologie et de Génétique ASBL, Gosselies, Belgium.ORCID 0000-0002-3236-0807
Deniz KaradurmusCentre de Génétique Humaine, Institut de Pathologie et de Génétique ASBL, Gosselies, Belgium.ORCID 0000-0001-8663-6357
Felicity CollinsDepartment of Medical Genomics/Clinical Genetics, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia.
Melissa CarterDepartment of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
Luis RohenaDivision of Medical Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
Marjolein H WillemsenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Charlotte W OckeloenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Sanne D KroftPluryn, Residential Care Setting, Groesbeek, The Netherlands.
Michael FieldGenetics of Learning Disability Service, Newcastle, NSW, Australia.ORCID 0000-0001-7455-934X
Francisco E R LaranjeiraCentro de Genética Médica Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal.
Ana M FortunaUnit for Multidisciplinary Research in Biomedicine, School of Medicine and Biomedical Sciences, Porto University, Porto, Portugal.
Ana R SoaresUnit for Multidisciplinary Research in Biomedicine, School of Medicine and Biomedical Sciences, Porto University, Porto, Portugal.ORCID 0000-0001-7817-9889
Vincent MichaudService de Génétique Médicale, CHU Bordeaux, Bordeaux, France.ORCID 0000-0002-5788-392X
Sophie NaudionService de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Sailaja GollaChild Neurology and Neurodevelopmental Medicine Thompson Autism Center, CHOC Hospital, Orange County, CA, USA.
David D WeaverIndiana University School of Medicine, Indianapolis, USA.
Lynne M BirdUniversity of California, San Diego, Rady Children's Hospital San Diego, San Diego, CA, USA.ORCID 0000-0003-4833-3747
Jennifer FriedmanUniversity of California, San Diego, Rady Children's Hospital San Diego, San Diego, CA, USA.
Virginia ClowesNorth West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, London, UK.
Shelagh JossWest of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK.
Laura PölslerCentrum Medische Genetica, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.ORCID 0000-0002-1796-2287
Philippe M CampeauCHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada.ORCID 0000-0001-9713-7107
Maria BlazoDivision Clinical Genetics Texas A&M University Health Science Center, College Station, TX, USA.
Emilia K BijlsmaDepartment of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Jill A RosenfeldMolecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Christian BeetzCentogene GmbH, Rostock, Germany.
Zöe PowisClinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
Kirsty McWalterGeneDx LLC, Gaithersburg, MA, USA.ORCID 0000-0002-1654-9036
Tracy BrandtGeneDx LLC, Gaithersburg, MA, USA.
Erin TortiGeneDx LLC, Gaithersburg, MA, USA.
Mikaël MathotNeuropediatric Unit, CHU UCL-Namur, Namur, Belgium.
Shekeeb S MohammadChildren's Hospital at Westmead, Sydney Children's Hospitals Network, Sydney, Australia.ORCID 0000-0003-1219-4781
Ruth ArmstrongEast Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, UK.
Vera M KalscheuerMax Planck Institute for Molecular Genetics, Group Development and Disease, Berlin, Germany. kalscheu@molgen.mpg.de.ORCID 0000-0001-6898-3259
University of Antwerp · BEHôpitaux Universitaires de Strasbourg · FRColumbia University Irving Medical Center · USHospital for Sick Children · CAHunter Genetics · AUInstitute of Pathology and Genetics · BEKing Faisal Specialist Hospital & Research Centre · SAMax Planck Institute for Molecular Genetics · DERadboud University Nijmegen · NLUNSW Sydney · AUAkron Children's Hospital · USCentre Hospitalier Universitaire de Tours · FRCentre National de la Recherche Scientifique · FRChildren's Hospital at Westmead · AUChildren's Mercy Hospital · USGreat Ormond Street Hospital · GBInstituto di Biofisica · ESKing Edward Memorial Hospital · AULinköping University · SELiverpool Hospital · AU
Funding
Department of HealthMedical Research Council MR/T007087/1Wellcome Trust
Abstract
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
Indexed as
Neurodevelopmental DisordersChloride ChannelsFemaleGenes, X-LinkedHumansMaleMutation, MissensePhenotypeChloride ChannelsCLCN4 protein, human
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