Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability
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Published:2017-10-11
Issue:1
Volume:55
Page:28-38
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ISSN:0022-2593
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Container-title:Journal of Medical Genetics
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language:en
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Short-container-title:J Med Genet
Author:
Hamilton Mark JORCID, Caswell Richard C, Canham Natalie, Cole Trevor, Firth Helen V, Foulds Nicola, Heimdal Ketil, Hobson Emma, Houge Gunnar, Joss Shelagh, Kumar Dhavendra, Lampe Anne Katrin, Maystadt Isabelle, McKay Victoria, Metcalfe Kay, Newbury-Ecob Ruth, Park Soo-Mi, Robert Leema, Rustad Cecilie F, Wakeling Emma, Wilkie Andrew O M, Study The Deciphering Developmental Disor, Twigg Stephen R F, Suri Mohnish
Abstract
IntroductionRecent 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.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur 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.ConclusionsThese 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.
Funder
Health Innovation Challenge Fund Wellcome Trust
Subject
Genetics (clinical),Genetics
Reference21 articles.
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