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Functional and clin...
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Palmer, Elizabeth E.Sydney Childrens Hosp Network, Australia; Univ New South Wales, Australia
(author)
Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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2022-11-16
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SPRINGERNATURE,2023
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:liu-190337
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-190337URI
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https://doi.org/10.1038/s41380-022-01852-9DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Funding Agencies|Fondazione AIRC per la Ricerca sul Cancro [IG 21558]; Italian Ministry for University and Research (MIUR) [PRIN 20174TB8KW]; FWO [1861419N]; Queen Elisabeth Medical Foundation; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [418081722, 433158657]; CPA grant [PG01217]; NHMRC Principal Research Fellowship [GNT1120615]; BICARE, Australia; King Salman Center for Disability Research [RG-2022-010, RG-2022-011]; MRC [MR/T007087/1]; GOSH Charity [VS0122]; Rosetrees Trust [CF2\100018]; NHMRC Investigator Grant [GNT20081]; Projekt DEAL; NIHR GOSH BRC
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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.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Pusch, MichaelCNR, Italy
(author)
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Picollo, AlessandraCNR, Italy
(author)
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Forwood, CaitlinSydney Childrens Hosp Network, Australia
(author)
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Nguyen, Matthew H.Univ New South Wales, Australia; Liverpool Hosp, Australia
(author)
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Suckow, VanessaMax Planck Inst Mol Genet, Germany
(author)
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Gibbons, JessicaMax Planck Inst Mol Genet, Germany
(author)
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Hoff, AlvaLinköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,CNR, Italy(Swepub:liu)n/a
(author)
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Sigfrid, LisaLinköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,CNR, Italy(Swepub:liu)n/a
(author)
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Megarbane, AndreLebanese Amer Univ, Lebanon; Inst Jerome Lejeune, France
(author)
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Nizon, MathildeNantes Univ, France; Nantes Univ, France
(author)
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Cogne, BenjaminNantes Univ, France; Nantes Univ, France
(author)
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Beneteau, ClaireNantes Univ, France
(author)
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Alkuraya, Fowzan S.King Faisal Specialist Hosp & Res Ctr, Saudi Arabia
(author)
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Chedrawi, AzizaKing Faisal Specialist Hosp & Res Ctr, Saudi Arabia
(author)
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Hashem, Mais O.King Faisal Specialist Hosp & Res Ctr, Saudi Arabia
(author)
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Stamberger, HannahVIB, Belgium; Antwerp Univ Hosp, Belgium
(author)
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Weckhuysen, SarahVIB, Belgium; Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium
(author)
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Vanlander, ArnaudGhent Univ Hosp, Belgium
(author)
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Ceulemans, BertenUniv Antwerp, Belgium
(author)
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Rajagopalan, SulekhaLiverpool Hosp, Australia
(author)
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Nunn, KennethChildrens Hosp Westmead, Australia
(author)
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Arpin, StephanieCtr Hosp Reg Univ Tours, France
(author)
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Raynaud, MartineCtr Hosp Reg Univ Tours, France
(author)
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Motter, Constance S.Akron Childrens Hosp, OH 44308 USA
(author)
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Ward-Melver, CatherineAkron Childrens Hosp, OH 44308 USA
(author)
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Janssens, KatrienUniv Antwerp, Belgium
(author)
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Meuwissen, MarijeUniv Antwerp, Belgium
(author)
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Beysen, DianeUniv Antwerp, Belgium
(author)
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Dikow, NicolaHeidelberg Univ, Germany
(author)
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Grimmel, MonaUniv Tubingen, Germany
(author)
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Haack, Tobias B.Univ Tubingen, Germany
(author)
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Clement, EmmaGreat Ormond St Hosp Sick Children, England
(author)
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McTague, AmyUCL Great Ormond St Inst Child Hlth, England; Great Ormond St Hosp Sick Children, England
(author)
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Hunt, DavidPrincess Anne Hosp, England
(author)
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Townshend, SharronKing Edward Mem Hosp, Australia
(author)
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Ward, MichelleKing Edward Mem Hosp, Australia
(author)
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Richards, Linda J.Washington Univ, MI USA; Univ Queensland, Australia
(author)
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Simons, CasMurdoch Childrens Res Inst, Australia; UNSW, Australia
(author)
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Costain, GregoryHosp Sick Children, Canada
(author)
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Dupuis, LucieHosp Sick Children, Canada
(author)
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Mendoza-Londono, RobertoHosp Sick Children, Canada
(author)
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Dudding-Byth, TracyGenet Learning Disabil Serv, Australia; Univ Newcastle, Australia
(author)
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Boyle, JackieGenet Learning Disabil Serv, Australia
(author)
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Saunders, CarolChildrens Mercy Hosp & Clin, MI USA; Univ Missouri, MI USA
(author)
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Fleming, EmilyChildrens Mercy Hosp & Clin, MI USA
(author)
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El Chehadeh, SalimaHop Univ Strasbourg, France; Univ Strasbourg, France; INSERM, France
(author)
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Spitz, Marie-AudeHop Univ Strasbourg, France
(author)
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Piton, AmelieHop Univ Strasbourg, France
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Gerard, BenedicteHop Univ Strasbourg, France
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Warde, Marie-Therese AbiHop Univ Strasbourg, France; CHU Strasbourg, France
(author)
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Rea, GillianNorthern Ireland Reg Genet Serv, North Ireland
(author)
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McKenna, CaoimheNorthern Ireland Reg Genet Serv, North Ireland
(author)
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Douzgou, SofiaHaukeland Hosp, Norway; Univ Manchester, England
(author)
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Banka, SiddharthUniv Manchester, England; Manchester Univ NHS Fdn Trust, England
(author)
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Akman, CigdemColumbia Univ, NY USA
(author)
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Bain, Jennifer M.Columbia Univ, NY USA
(author)
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Sands, Tristan T.Columbia Univ, NY USA
(author)
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Wilson, Golder N.Texas Tech Hlth Sci Ctr Lubbock, TX USA; KinderGenome Med Genet, TX USA
(author)
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Silvertooth, Erin J.Texas Sports Psychiat & Integrat Hlth, TX USA
(author)
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Miller, LaurenHillcrest Internal Med, TX USA
(author)
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Lederer, DamienInst Pathol & Genet ASBL, Belgium
(author)
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Sachdev, RaniSydney Childrens Hosp Network, Australia; Univ New South Wales, Australia
(author)
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Macintosh, RebeccaSydney Childrens Hosp Network, Australia; Univ New South Wales, Australia
(author)
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Monestier, OlivierInst Pathol & Genet ASBL, Belgium
(author)
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Karadurmus, DenizInst Pathol & Genet ASBL, Belgium
(author)
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Collins, FelicityRoyal Prince Alfred Hosp, Australia
(author)
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Carter, MelissaChildrens Hosp Eastern Ontario, Canada
(author)
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Rohena, LuisSan Antonio Mil Med Ctr, TX USA; UT Hlth San Antonio, TX USA
(author)
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Willemsen, Marjolein H.Radboud Univ Nijmegen Med Ctr, Netherlands
(author)
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Ockeloen, Charlotte W.Radboud Univ Nijmegen Med Ctr, Netherlands
(author)
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Pfundt, RolphRadboud Univ Nijmegen Med Ctr, Netherlands
(author)
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Kroft, Sanne D.Pluryn, Netherlands
(author)
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Field, MichaelGenet Learning Disabil Serv, Australia
(author)
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Laranjeira, Francisco E. R.Ctr Hosp Univ Porto, Portugal
(author)
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Fortuna, Ana M.Univ Porto, Portugal
(author)
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Soares, Ana R.Univ Porto, Portugal
(author)
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Michaud, VincentCHU Bordeaux, France; Bordeaux Univ, France
(author)
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Naudion, SophieCHU Bordeaux, France
(author)
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Golla, SailajaCHOC Hosp, CA USA
(author)
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Weaver, David D.Indiana Univ Sch Med, IN 46202 USA
(author)
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Bird, Lynne M.Univ Calif San Diego, CA 92103 USA
(author)
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Friedman, JenniferUniv Calif San Diego, CA 92103 USA
(author)
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Clowes, VirginiaLondon North West Univ Healthcare NHS Trust, England; Imperial Coll London, England
(author)
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Joss, ShelaghQueen Elizabeth Univ Hosp, Scotland
(author)
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Polsler, LauraUniv Ziekenhuis Brussel, Belgium
(author)
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Campeau, Philippe M.Univ Montreal, Canada
(author)
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Blazo, MariaTexas A&M Univ, TX USA
(author)
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Bijlsma, Emilia K.Leiden Univ Med Ctr, Netherlands
(author)
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Rosenfeld, Jill A.Baylor Coll Med, TX 77030 USA; Baylor Genet Labs, TX USA
(author)
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Beetz, ChristianCentogene GmbH, Germany
(author)
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Powis, ZoeAmbry Genet, CA USA
(author)
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McWalter, KirstyGeneDx LLC, MA USA
(author)
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Brandt, TracyGeneDx LLC, MA USA
(author)
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Torti, ErinGeneDx LLC, MA USA
(author)
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Mathot, MikaelCHU UCL Namur, Belgium
(author)
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Mohammad, Shekeeb S.Childrens Hosp Westmead, Australia
(author)
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Armstrong, RuthAddenbrookes Hosp, England
(author)
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Kalscheuer, Vera M.Max Planck Inst Mol Genet, Germany
(author)
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Sydney Childrens Hosp Network, Australia; Univ New South Wales, AustraliaCNR, Italy
(creator_code:org_t)
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In:Molecular Psychiatry: SPRINGERNATURE28:2, s. 668-6971359-41841476-5578
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Soares, Ana R.
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Michaud, Vincent
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Naudion, Sophie
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Weaver, David D.
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