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Neurol Genet. 2017 Dec 15;3(6):e200. doi: 10.1212/NXG.0000000000000200. eCollection 2017 Dec.

CDKL5 variants: Improving our understanding of a rare neurologic disorder.

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Institute of Neuroscience & Psychology (R.D.H., S.R.C.), University of Glasgow, UK, Drs. Hector and Cobb are currently with the Patrick Wild Centre and Centre for Discovery Brain Science, University of Edinburgh, UK; Group Development and Disease (V.M.K., F.H.), Max Planck Institute for Molecular Genetics, Berlin, Germany; Telethon Kids Institute (H.L., J.D.), The University of Western Australia, Perth, Western Australia; School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia; Institute of Medical Genetics (A.C.), School of Medicine, Cardiff University, Cardiff, Wales, UK; Departments of Pediatrics, Pharmacology, Neurology and Otolaryngology (T.A.B.), University of Colorado School of Medicine, Aurora, CO; Paedriatic Neuroscience (J.A., M.P.), Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain; Hospital Sant Joan de Déu Barcelona (J.A.), Esplugues de Llobregat, Spain; CIBERER (J.A.), Barcelona, Spain; Neuropediatrics (M.P.), Fundació Sant Joan de Déu, Esplugues de Llobregat, Spain; and School of Life Sciences (M.E.S.B.), College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.



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.


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.


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.


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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