Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.

TitlePhenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.
Publication TypeJournal Article
Year of Publication2017
AuthorsBostwick, BL, McLean, S, Posey, JE, Streff, HE, Gripp, KW, Blesson, A, Powell-Hamilton, N, Tusi, J, Stevenson, DA, Farrelly, E, Hudgins, L, Yang, Y, Xia, F, Wang, X, Liu, P, Walkiewicz, M, McGuire, M, Grange, DK, Andrews, MV, Hummel, M, Madan-Khetarpal, S, Infante, E, Coban-Akdemir, Z, Miszalski-Jamka, K, Jefferies, JL, Rosenfeld, JA, Emrick, L, Nugent, KM, Lupski, JR, Belmont, JW, Lee, B, Lalani, SR
Corporate AuthorsMembers of the Undiagnosed Diseases Network
JournalGenome Med
Volume9
Issue1
Pagination73
Date Published2017 Aug 14
ISSN1756-994X
KeywordsAdolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome
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.

DOI10.1186/s13073-017-0463-8
Alternate JournalGenome Med
PubMed ID28807008
PubMed Central IDPMC5557075
Grant ListU01 HG007709 / HG / NHGRI NIH HHS / United States