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.
Highlights
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
Congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD) is a newly described syndrome caused by de novo variants in CDK13 [1]
In order to provide comprehensive phenotypic and molecular characterisation, additional individuals with CDK13 pathogenic variants were recruited from clinical exome sequencing laboratory cohorts and one individual was ascertained through review of the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) exome variant database
Summary
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. Congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD) is a newly described syndrome caused by de novo variants in CDK13 [1]. The syndrome was discovered as part of a large exome sequencing cohort of 1891 individuals with congenital heart defects. All seven initially reported children had structural congenital heart disease with either atrial and/or ventricular septal defects or pulmonary valve abnormalities. A subsequent report identified additional individuals with de novo variants in CDK13 that reached genomewide significance in a second large exome sequencing cohort of 4293 families containing individuals with developmental disorders [2]. Dysmorphology and organ-specific detailed phenotypic information was not available
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