Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

CAUSES Study

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2 Citations (Scopus)

Abstract

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl channels and Cl/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3−/− mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Original languageEnglish
Pages (from-to)1450-1465
Number of pages16
JournalAmerican Journal of Human Genetics
Volume108
Issue number8
DOIs
Publication statusPublished - 5 Aug 2021

Bibliographical note

Funding Information:
This work is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR068429-01 to P.B.A.), the National Institutes of Health (T32HD098061 to A.R.D.), the Deutsche Forschungsgemeinschaft (FOR 2652 (Je164/14-1,2) and Exc257 ?NeuroCure?), the Prix Louis-Jeantet de M?decine to T.J.J. and by a grant from the Fondazione AIRC per la Ricerca sul Cancro (grant # IG 21558) and the Italian Research Ministry (PRIN 20174TB8KW) to M.P. This work was supported in part by the Manton Center for Orphan Disease Research and Sanger sequencing performed by the Boston Children's Hospital IDDRC Molecular Genetics Core Facility supported by NIH award U54HD090255 from the National Institute of Child Health and Human Development. This work was also supported by the Spanish Ministerio de Ciencia e Innovaci?n(MICINN) (RTI2018-093493-B-I00 to R.E.) and R.E. is a recipient of an ICREA Academia prize. The investigators of the CAUSES Study include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman. CAUSES Study was funded by Mining for Miracles, British Columbia Children's Hospital Foundation, and Genome British Columbia. Sequencing and analysis for individual 6 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grants UM1 HG008900 and R01 HG009141 and by the Chan Zuckerberg Initiative to the Rare Genomes Project.

Funding Information:
Sequencing and analysis for individual 6 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grants UM1 HG008900 and R01 HG009141 and by the Chan Zuckerberg Initiative to the Rare Genomes Project .

Funding Information:
This work is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( R01AR068429-01 to P.B.A.), the National Institutes of Health ( T32HD098061 to A.R.D.), the Deutsche Forschungsgemeinschaft ( FOR 2652 (Je164/14-1,2) and Exc257 “NeuroCure”), the Prix Louis-Jeantet de Médecine to T.J.J., and by a grant from the Fondazione AIRC per la Ricerca sul Cancro (grant # IG 21558 ) and the Italian Research Ministry ( PRIN 20174TB8KW ) to M.P. This work was supported in part by the Manton Center for Orphan Disease Research and Sanger sequencing performed by the Boston Children’s Hospital IDDRC Molecular Genetics Core Facility supported by NIH award U54HD090255 from the National Institute of Child Health and Human Development . This work was also supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) ( RTI2018-093493-B-I00 to R.E.) and R.E. is a recipient of an ICREA Academia prize. The investigators of the CAUSES Study include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman. CAUSES Study was funded by Mining for Miracles , British Columbia Children’s Hospital Foundation , and Genome British Columbia .

Publisher Copyright:
© 2021 American Society of Human Genetics

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