Hector Ralph D, Kalscheuer Vera M, Hennig Friederike, Leonard Helen, Downs Jenny, Clarke Angus, Benke Tim A, Armstrong Judith, Pineda Mercedes, Bailey Mark E S, Cobb Stuart R
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.
Neurol Genet. 2017 Dec 15;3(6):e200. doi: 10.1212/NXG.0000000000000200. eCollection 2017 Dec.
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 gene.
We analyzed all known potentially pathogenic variants by combining data from large-scale population sequencing studies with 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 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.
在人群测序数据以及该基因最新特征描述的背景下，为解读一种罕见神经系统疾病——CDKL5缺乏症中的基因变异提供新见解。
我们通过整合大规模人群测序研究的数据与来自新的及所有可用临床队列的变异，分析了所有已知的潜在致病变异，并结合计算方法来预测致病性。
该研究鉴定出了几个可重新分类为良性或可能良性的变异。随着新变异的加入，我们证实致病变异聚集在CDKL5的催化结构域，并将一个所谓的错义变异重新分类为具有剪接后果。我们提供了进一步的证据表明最后3个外显子中的错义变异可能是良性的，对疾病病理不重要。我们还描述了这些外显子内的良性剪接和无义变异，提示异构体hCDKL5_5可能对神经功能影响很小或没有影响。我们还利用现有数据对CDKL5缺乏症的最低发病率做了初步估计。
这些发现对基因诊断有影响，为重新分类先前认为会导致CDKL5缺乏症的特定变异提供了证据。总之，这些分析支持这样一种观点，即人类主要的脑异构体（hCDKL5_1）对正常神经发育至关重要，且催化结构域是主要的功能结构域。
