Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

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 CeulemansSulekha 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 Saunders, Emily Fleming, 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

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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.

Original languageEnglish
Pages (from-to)668-697
Number of pages30
JournalMolecular Psychiatry
Issue number2
Early online date16 Nov 2022
Publication statusPublished - Feb 2023


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