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| Item Type: | Article |
|---|---|
| Title: | De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females |
| Creators Name: | Palmer, E.E. and Stuhlmann, T. and Weinert, S. and Haan, E. and Van Esch, H. and Holvoet, M. and Boyle, J. and Leffler, M. and Raynaud, M. and Moraine, C. and van Bokhoven, H. and Kleefstra, T. and Kahrizi, K. and Najmabadi, H. and Ropers, H.H. and Delgado, M.R. and Sirsi, D. and Golla, S. and Sommer, A. and Pietryga, M.P. and Chung, W.K. and Wynn, J. and Rohena, L. and Bernardo, E. and Hamlin, D. and Faux, B.M. and Grange, D.K. and Manwaring, L. and Tolmie, J. and Joss, S. and Cobben, J.M. and Duijkers, F.A.M. and Goehringer, J.M. and Challman, T.D. and Hennig, F. and Fischer, U. and Grimme, A. and Suckow, V. and Musante, L. and Nicholl, J. and Shaw, M. and Lodh, S.P. and Niu, Z. and Rosenfeld, J.A. and Stankiewicz, P. and Jentsch, T.J. and Gecz, J. and Field, M. and Kalscheuer, V.M. |
| Abstract: | Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family. |
| Keywords: | Chloride Channels, Epilepsy, Epileptic Syndromes, Family, Germ-Line Mutation, Intellectual Disability, Mutation, Oocytes, Pedigree, Phenotype, Syndrome, X-Linked Genes, X-Linked Genetic Diseases, White Matter, Animals, Xenopus laevis |
| Source: | Molecular Psychiatry |
| ISSN: | 1359-4184 |
| Publisher: | Nature Publishing Group |
| Volume: | 23 |
| Number: | 2 |
| Page Range: | 222-230 |
| Date: | February 2018 |
| Official Publication: | https://doi.org/10.1038/mp.2016.135 |
| PubMed: | View item in PubMed |
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