Elizabeth E. Palmer
Michael Pusch
Alessandra Picollo
Caitlin Forwood
Matthew H. Nguyen
Vanessa Suckow
Jessica Gibbons
Alva Hoff
Lisa Sigfrid
Andre Megarbane
Mathilde Nizon
Benjamin Cogné
Claire Beneteau
Fowzan S. Alkuraya
Aziza Chedrawi
Mais O. Hashem
Hannah Stamberger
Sarah Weckhuysen
Arnaud Vanlander
Berten Ceulemans
Sulekha Rajagopalan
Kenneth Nunn
Stéphanie Arpin
Martine Raynaud
Constance S. Motter
Catherine Ward-Melver
Katrien Janssens
Marije Meuwissen
Diane Beysen
Nicola Dikow
Mona Grimmel
Tobias B. Haack
Emma Clement
Amy McTague
David Hunt
Sharron Townshend
Michelle Ward
Linda J. Richards
Cas Simons
Gregory Costain
Lucie Dupuis
Roberto Mendoza-Londono
Tracy Dudding-Byth
Jackie Boyle
Carol J. Saunders, Children's Mercy HospitalFollow
Emily Fleming, Children's Mercy Kansas City
Salima El Chehadeh
Marie-Aude Spitz
Amelie Piton
Bénédicte Gerard
Marie-Thérèse Abi Warde
Gillian Rea
Caoimhe McKenna
Sofia Douzgou
Siddharth Banka
Cigdem Akman
Jennifer M. Bain
Tristan T. Sands
Golder N. Wilson
Erin J. Silvertooth
Lauren Miller
Damien Lederer
Rani Sachdev
Rebecca Macintosh
Olivier Monestier
Deniz Karadurmus
Felicity Collins
Melissa Carter
Luis Rohena
Marjolein H. Willemsen
Charlotte W. Ockeloen
Rolph Pfundt
Sanne D. Kroft
Michael Field
Francisco E R Laranjeira
Ana M. Fortuna
Ana R. Soares
Vincent Michaud
Sophie Naudion
Sailaja Golla
David D. Weaver
Lynne M. Bird
Jennifer Friedman
Virginia Clowes
Shelagh Joss
Laura Pölsler
Philippe M. Campeau
Maria Blazo
Emilia K. Bijlsma
Jill A. Rosenfeld
Christian Beetz
Zöe Powis
Kirsty McWalter
Tracy Brandt
Erin Torti
Mikaël Mathot
Shekeeb S. Mohammad
Ruth Armstrong
Vera M. Kalscheuer

Document Type


Publication Date



DOI: 10.1038/s41380-022-01852-9; PMCID: PMC9908558


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.

Journal Title

Molecular psychiatry





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Last Page


MeSH Keywords

Male; Female; Humans; Neurodevelopmental Disorders; Mutation, Missense; Genes, X-Linked; Phenotype; Chloride Channels


Neurodevelopmental Disorders; Missense Mutation; X-Linked Genes; Phenotype; Chloride Channels


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