RT Journal Article SR Electronic T1 Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2017-104620 DO 10.1136/jmedgenet-2017-104620 A1 Mark J Hamilton A1 Richard C Caswell A1 Natalie Canham A1 Trevor Cole A1 Helen V Firth A1 Nicola Foulds A1 Ketil Heimdal A1 Emma Hobson A1 Gunnar Houge A1 Shelagh Joss A1 Dhavendra Kumar A1 Anne Katrin Lampe A1 Isabelle Maystadt A1 Victoria McKay A1 Kay Metcalfe A1 Ruth Newbury-Ecob A1 Soo-Mi Park A1 Leema Robert A1 Cecilie F Rustad A1 Emma Wakeling A1 Andrew O M Wilkie A1 The Deciphering Developmental Disorders Study A1 Stephen R F Twigg A1 Mohnish Suri YR 2017 UL http://jmg.bmj.com/content/early/2017/10/11/jmedgenet-2017-104620.abstract AB 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.