Articolo in rivista, 2022, ENG, 10.1038/s41380-022-01852-9
Palmer, Elizabeth E.; Pusch, Michael; Picollo, Alessandra; Forwood, Caitlin; Nguyen, Matthew H.; Suckow, Vanessa; Gibbons, Jessica; Hoff, Alva; Sigfrid, Lisa; Megarbane, Andre; Nizon, Mathilde; Cogne, Benjamin; Beneteau, Claire; Alkuraya, Fowzan S.; Chedrawi, Aziza; Hashem, Mais O.; Stamberger, Hannah; Weckhuysen, Sarah; Vanlander, Arnaud; Ceulemans, Berten; Rajagopalan, Sulekha; Nunn, Kenneth; Arpin, Stephanie; Raynaud, Martine; Motter, Constance S.; Ward-Melver, Catherine; Janssens, Katrien; Meuwissen, Marije; Beysen, Diane; Dikow, Nicola; Grimmel, Mona; Haack, Tobias B.; Clement, Emma; McTague, Amy; Hunt, David; Townshend, Sharron; Ward, Michelle; Richards, Linda J.; Simons, Cas; Costain, Gregory; Dupuis, Lucie; Mendoza-Londono, Roberto; Dudding-Byth, Tracy; Boyle, Jackie; Saunders, Carol; Fleming, Emily; El Chehadeh, Salima; Spitz, Marie-Aude; Piton, Amelie; Gerard, Benedicte; Warde, Marie-Therese Abi; Rea, Gillian; McKenna, Caoimhe; Douzgou, Sofia; Banka, Siddharth; Akman, Cigdem; Bain, Jennifer M.; Sands, Tristan T.; Wilson, Golder N.; Silvertooth, Erin J.; Miller, Lauren; Lederer, Damien; Sachdev, Rani; Macintosh, Rebecca; Monestier, Olivier; Karadurmus, Deniz; Collins, Felicity; Carter, Melissa; Rohena, Luis; Willemsen, Marjolein H.; Ockeloen, Charlotte W.; Pfundt, Rolph; Kroft, Sanne D.; Field, Michael; Laranjeira, Francisco E. R.; Fortuna, Ana M.; Soares, Ana R.; Michaud, Vincent; Naudion, Sophie; Golla, Sailaja; Weaver, David D.; Bird, Lynne M.; Friedman, Jennifer; Clowes, Virginia; Joss, Shelagh; Polsler, Laura; Campeau, Philippe M.; Blazo, Maria; Bijlsma, Emilia K.; Rosenfeld, Jill A.; Beetz, Christian; Powis, Zoe; McWalter, Kirsty; Brandt, Tracy; Torti, Erin; Mathot, Mikael; Mohammad, Shekeeb S.; Armstrong, Ruth; Kalscheuer, Vera M.
Sydney Childrens Hosp Network; Univ New South Wales; CNR; Liverpool Hosp; Max Planck Inst Mol Genet; Linkoping Univ; Lebanese Amer Univ; Inst Jerome Lejeune; Nantes Univ; Nantes Univ; King Faisal Specialist Hosp & Res Ctr; King Faisal Specialist Hosp & Res Ctr; VIB; Antwerp Univ Hosp; Univ Antwerp; Ghent Univ Hosp; Univ Antwerp; Childrens Hosp Westmead; Ctr Hosp Reg Univ Tours; Akron Childrens Hosp; Univ Antwerp; Univ Antwerp; Heidelberg Univ; Univ Tubingen; Great Ormond St Hosp Sick Children; UCL Great Ormond St Inst Child Hlth; Great Ormond St Hosp Sick Children; Princess Anne Hosp; King Edward Mem Hosp; Washington Univ; Univ Queensland; Murdoch Childrens Res Inst; UNSW; Hosp Sick Children; Genet Learning Disabil Serv; Univ Newcastle; Childrens Mercy Hosp & Clin; Univ Missouri; Childrens Mercy Hosp & Clin; Hop Univ Strasbourg; Univ Strasbourg; INSERM; Hop Univ Strasbourg; Hop Univ Strasbourg; CHU Strasbourg; Northern Ireland Reg Genet Serv; Haukeland Hosp; Univ Manchester; Manchester Univ NHS Fdn Trust; Columbia Univ; Texas Tech Hlth Sci Ctr Lubbock; KinderGenome Med Genet; Texas Sports Psychiat & Integrat Hlth; Hillcrest Internal Med; Inst Pathol & Genet ASBL; Royal Prince Alfred Hosp; Childrens Hosp Eastern Ontario; San Antonio Mil Med Ctr; UT Hlth San Antonio; Radboud Univ Nijmegen Med Ctr; Pluryn; Ctr Hosp Univ Porto; Univ Porto; CHU Bordeaux; Bordeaux Univ; CHOC Hosp; Indiana Univ Sch Med; Univ Calif San Diego; London North West Univ Healthcare NHS Trust; Imperial Coll London; Queen Elizabeth Univ Hosp; Univ Ziekenhuis Brussel; Univ Montreal; Texas A&M Univ; Leiden Univ Med Ctr; Baylor Coll Med; Baylor Genet Labs; Centogene GmbH; Ambry Genet; GeneDx LLC; CHU UCL Namur; Addenbrookes Hosp
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.
Molecular psychiatry
Pusch Michael, Picollo Alessandra
ID: 476058
Year: 2022
Type: Articolo in rivista
Creation: 2023-01-09 13:55:24.000
Last update: 2023-02-13 13:06:04.000
CNR authors
CNR institutes
External IDs
CNR OAI-PMH: oai:it.cnr:prodotti:476058
DOI: 10.1038/s41380-022-01852-9
ISI Web of Science (WOS): 000884630500002