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

Abstract

BackgroundDe 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.MethodsTo 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.ResultsWe 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.ConclusionsHere 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0463-8) contains supplementary material, which is available to authorized users.

De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review

“…Localization of the amino‐acid (aa) residue substitutions in the CDK13 protein of all presently reported and published individuals, and transcript analysis of a splice‐site mutation in CDK13 . (A) Schematic localization of all presently and earlier reported de novo CDK13 variants.…”

“…Over all the variants that have been reported so far, this is the most frequently encountered variant in individuals with the CDK13 syndrome (17/40, 43%). Interestingly, both Bostwick et al and Hamilton et al report another variant at this amino‐acid position (c.2525A > G, p.Asn842Asp) which introduces a negative charge in the active site of the protein kinase domain. The variants leading to p.Arg737Cys and p.Arg880Cys were not reported before and locate in the kinase domain as all other reported missense variants do.…”

“…Recently, de novo missense variants located in the kinase domain of CDK13 have been reported . Sifrim et al describe 7 individuals with congenital heart defects, mainly of the ventral and atrial septa .…”

“…Common phenotypic characteristics of these individuals included ID and dysmorphic facial characteristics. Bostwick et al describe another 9 individuals, showing a similar phenotype with developmental delay (DD)/ID, congenital heart defects, hypotonia and facial dysmorphisms. It is of note that all reported variants in that study are de novo missense variants, with one recurrent variant (p.Asn842Ser) reported in 7 non‐related individuals.…”

“…It is of note that all reported variants in that study are de novo missense variants, with one recurrent variant (p.Asn842Ser) reported in 7 non‐related individuals. Hamilton et al provide extensive clinical information on 16 cases, which included an update on 13 previously reported individuals …”