@article{01GSSG03KWN73EZB7N9ZD2YGRK,
  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.}},
  author       = {{Palmer, Elizabeth E. and  Pusch, Michael and  Picollo, Alessandra and  Forwood, Caitlin and  Nguyen, Matthew H. and  Suckow, Vanessa and  Gibbons, Jessica and  Hoff, Alva and  Sigfrid, Lisa and  Megarbane, Andre and  Nizon, Mathilde and  Cogne, Benjamin and  Beneteau, Claire and  Alkuraya, Fowzan S. and  Chedrawi, Aziza and  Hashem, Mais O. and  Stamberger, Hannah and  Weckhuysen, Sarah and Vanlander, Arnaud and  Ceulemans, Berten and  Rajagopalan, Sulekha and  Nunn, Kenneth and  Arpin, Stephanie and  Raynaud, Martine and  Motter, Constance S. and  Ward-Melver, Catherine and  Janssens, Katrien and  Meuwissen, Marije and  Beysen, Diane and  Dikow, Nicola and  Grimmel, Mona and  Haack, Tobias B. and  Clement, Emma and  McTague, Amy and  Hunt, David and  Townshend, Sharron and  Ward, Michelle and  Richards, Linda J. and  Simons, Cas and  Costain, Gregory and  Dupuis, Lucie and  Mendoza-Londono, Roberto and  Dudding-Byth, Tracy and  Boyle, Jackie and  Saunders, Carol and  Fleming, Emily and  El Chehadeh, Salima and  Spitz, Marie-Aude and  Piton, Amelie and  Gerard, Benedicte and  Warde, Marie-Therese Abi and  Rea, Gillian and  McKenna, Caoimhe and  Douzgou, Sofia and  Banka, Siddharth and  Akman, Cigdem and  Bain, Jennifer M. and  Sands, Tristan T. and  Wilson, Golder N. and  Silvertooth, Erin J. and  Miller, Lauren and  Lederer, Damien and  Sachdev, Rani and  Macintosh, Rebecca and  Monestier, Olivier and  Karadurmus, Deniz and  Collins, Felicity and  Carter, Melissa and  Rohena, Luis and  Willemsen, Marjolein H. and  Ockeloen, Charlotte W. and  Pfundt, Rolph and  Kroft, Sanne D. and  Field, Michael and  Laranjeira, Francisco E. R. and  Fortuna, Ana M. and  Soares, Ana R. and  Michaud, Vincent and  Naudion, Sophie and  Golla, Sailaja and  Weaver, David D. and  Bird, Lynne M. and  Friedman, Jennifer and  Clowes, Virginia and  Joss, Shelagh and  Polsler, Laura and  Campeau, Philippe M. and  Blazo, Maria and  Bijlsma, Emilia K. and  Rosenfeld, Jill A. and  Beetz, Christian and  Powis, Zoe and  McWalter, Kirsty and  Brandt, Tracy and  Torti, Erin and  Mathot, Mikael and  Mohammad, Shekeeb S. and  Armstrong, Ruth and  Kalscheuer, Vera M.}},
  issn         = {{1359-4184}},
  journal      = {{MOLECULAR PSYCHIATRY}},
  keywords     = {{LINKED MENTAL-RETARDATION,LYSOSOMAL STORAGE DISEASE,CLC CHLORIDE,CHANNELS,EXCHANGER,GENE,ASSOCIATION,DISRUPTION,PHENOTYPE,VARIANTS,MUTATION}},
  language     = {{eng}},
  pages        = {{668--697}},
  title        = {{Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition}},
  url          = {{http://doi.org/10.1038/s41380-022-01852-9}},
  volume       = {{28}},
  year         = {{2023}},
}

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