Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability

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.

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 .…”

“…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 …”

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

“…Liquid droplets diameter in the presence of A1 and A2 aptamers. A2 presents identical sequences to DDHD1, SLC24A4, and CDK13 mRNA, which are involved in neurodegeneration, 67 Alzheimer's disease 68 and intellectual disability, 69 respectively. Scale bar, 10 µm 90-113) and C-terminal regions (residues 194-231) are predicted to be mostly disordered by several commonly used per-residue disorder predictors, such as members of the PONDR family, PONDR VLXT, 52 PONDR VL3, 53 PONDR VSL2, 54 and PONDR FIT 55 and IUPred web server for prediction of short and long disordered regions.…”