Document Type
Article
Publication Date
2017
College/Unit
School of Medicine
Department/Program/Center
Pediatrics
Abstract
Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.
Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.
Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.
Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.
Keywords: CDK13, CHDFIDD, De novo variant, Neurodevelopmental disorders, Agenesis of the corpus callosum, Hypertelorism, Developmental delay, Cyclin-dependent kinase, Undiagnosed Diseases Network
Digital Commons Citation
Bostwick, Bret L.; McLean, Scott; Posey, Jennifer E.; Streff, Haley E.; Gripp, Karen W.; Blesson, Alyssa; Powell-Hamilton, Nina; Tusi, Jessica; Stevenson, David A.; Farrelly, Ellyn; Hudgins, Louanne; Yang, Yaping; Xia, Fan; Wang, Xia; Liu, Pengfei; Walkiewicz, Magdalena; McGuire, Marianne; Grange, Dorothy K.; Andrews, Marisa V.; Hummel, Marybeth; Madan-Khetarpal, Suneeta; Infante, Elena; Coban-Akdemir, Zeynep; Miszalski-Jamka, Karol; Jefferies, John L.; Rosenfeld, Jill A.; Emrick, Lisa; Nugent, Kimberly M.; Lupski, James R.; Belmont, John W.; Lee, Brendan; and Lalani, Seema R., "Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders" (2017). Faculty & Staff Scholarship. 1477.
https://researchrepository.wvu.edu/faculty_publications/1477
Source Citation
Bostwick, B.L., McLean, S., Posey, J.E. et al. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med 9, 73 (2017). https://doi.org/10.1186/s13073-017-0463-8
Comments
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.