Article Text
Abstract
Introduction Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.
Methods Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.
Results Our cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.
Conclusions These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.
- cdk13
- congenital heart defects
- ohdo syndrome
- protein kinases
- exome sequencing
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Footnotes
MJH and RCC contributed equally.
Contributors MJH and RC prepared the manuscript for publication, in consultation with MS. Comparative protein modelling and thermodynamic stability calculations were completed by RC. MS conceived and coordinated the project and is responsible for the overall content as guarantor. SRFT completed the expression studies relating to the splice site variant, had a key role in generating and interpreting exome data for patient 11 and contributed intellectually to re-drafting of the manuscript. All other authors had a role in generating the clinical and/or genetic data for the patients presented, as well as contributing intellectually to re-drafting of the manuscript. All authors have seen and approved the final manuscript.
Funding The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study also makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of DECIPHER data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk; funding for this project was provided by the Wellcome Trust. Work carried out in Oxford for the present study was funded by Wellcome Trust Project Grant 093329 to SRFT and Professor AOMW, and Senior Investigator Award 102731 to Professor AOMW.
Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The DDD Study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). Ethical approval for work carried out at the Weatherall Institute, Oxford, was granted by the Riverside Research Ethics Committee (reference 09/H0706/20). Genetic data regarding patient 12 were produced as part of a clinical diagnostic service.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data relating to the study are available within the manuscript and accompanying online supplementary files.