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  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

Palmer, E. E., Stuhlmann, T., Weinert, S., Haan, E., van Esch, H., Holvoet, M., et al. (2018). 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. Molecular Psychiatry, 23(2), 222-230. doi:10.1038/mp.2016.135.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-16FB-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5856-A
Genre: Journal Article

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 Creators:
Palmer, E. E., Author
Stuhlmann, T., Author
Weinert, S., Author
Haan, E., Author
van Esch, H., Author
Holvoet, M., Author
Boyle, J., Author
Leffler, M., Author
Raynaud, M., Author
Moraine, C., Author
van Bokhoven, H., Author
Kleefstra, T., Author
Kahrizi, K., Author
Najmabadi, H., Author
Ropers, H.-H.1, Author              
Delgado, M. R., Author
Sirsi, D., Author
Golla, S., Author
Sommer, A., Author
Pietryga, M. P., Author
Chung, W. K., AuthorWynn, J., AuthorRohena, L., AuthorBernardo, E., AuthorHamlin, D., AuthorFaux, B. M., AuthorGrange, D. K., AuthorManwaring, L., AuthorTolmie, J., AuthorJoss, S., AuthorStudy, D. D. D., AuthorCobben, J. M., AuthorDuijkers, F. A. M., AuthorGoehringer, M., AuthorChallman, T. D., AuthorHennig, F.2, Author              Fischer, U.3, Author              Grimme, A., AuthorSuckow, V.3, Author              Musante, L., AuthorNicholl, J., AuthorShaw, M., AuthorLodh, S. P., AuthorNiu, Z., AuthorRosenfeld, A., AuthorStankiewicz, P., AuthorJentsch, T. H., AuthorGecz, J., AuthorField, M., AuthorKalscheuer, V. M.2, Author               more..
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 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.

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Language(s): eng - English
 Dates: 2016-06-202016-08-232018-02
 Publication Status: Published in print
 Pages: 9
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/mp.2016.135
 Degree: -

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Title: Molecular Psychiatry
Source Genre: Journal
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Publ. Info: Houndmills, Hampshire, UK : Stockton Press
Pages: - Volume / Issue: 23 (2) Sequence Number: - Start / End Page: 222 - 230 Identifier: ISSN: 1359-4184
CoNE: /journals/resource/954925619131