CDKL5 variants: improving our understanding of a rare neurological disorder

Hector, R. D. et al. (2017) CDKL5 variants: improving our understanding of a rare neurological disorder. Neurology Genetics, 3(6), e200. (doi: 10.1212/NXG.0000000000000200) (PMID:29264392) (PMCID:PMC5732004)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cobb, Dr Stuart and Hector, Dr Ralph and Bailey, Dr Mark
Authors: Hector, R. D., Kalscheuer, V. M., Hennig, F., Leonard, H., Downs, J., Clarke, A., Benke, T. A., Armstrong, J., Pineda, M., Bailey, M. E.S., and Cobb, S. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Neurology Genetics
Publisher:Lippincott, Williams & Wilkins
ISSN:2376-7839
ISSN (Online):2376-7839
Published Online:15 December 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Neurology Genetics 3(6): e200
Publisher Policy:Reproduced under a Creative Commons License

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