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  CDKL5 variants: Improving our understanding of a rare neurologic disorder

Hector, R. D., Kalscheuer, V. M., Hennig, F., Leonard, H., Downs, J., Clarke, A., et al. (2017). CDKL5 variants: Improving our understanding of a rare neurologic disorder. Neurology Genetics, 3(6): e200. doi:10.1212/NXG.0000000000000200.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-CE6B-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-598C-D
Genre: Journal Article

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 Creators:
Hector, R. D., Author
Kalscheuer, V. M.1, Author              
Hennig, F.1, Author              
Leonard, H., Author
Downs, J., Author
Clarke, A., Author
Benke, T. A., Author
Armstrong, J., Author
Pineda, M., Author
Bailey, M. E. S., Author
Cobb, S. R., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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 Abstract: Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

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Language(s): eng - English
 Dates: 2017-09-282017-12
 Publication Status: Published online
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 Identifiers: DOI: 10.1212/NXG.0000000000000200
ISSN: 2376-7839 (Electronic)
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Title: Neurology Genetics
  Alternative Title : Neurology. Genetics
Source Genre: Journal
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Publ. Info: Wolters Kluwer
Pages: - Volume / Issue: 3 (6) Sequence Number: e200 Start / End Page: - Identifier: -