Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability
Open accessAbstract
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.
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Missense de novo mutations in all four enriched domain families have previously been associated with developmental disorders.
“Missense DNMs in all four enriched domain families have previously been associated with DD (Supplementary Table 8)16–18.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [18]
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Evidence for 28 genetic disorders discovered by combining healthcare and research data
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- Authors
- Hamilton, M. J., Caswell, R. C., Canham, N., Cole, T., Firth, H. V., Foulds, N., Heimdal, K., Hobson, E., Houge, G., Joss, S., Kumar, D., Lampe, A. K., Maystadt, I., McKay, V., Metcalfe, K., Newbury-Ecob, R., Park, S.-M., Robert, L., Rustad, C. F., Wakeling, E., Wilkie, A. O. M., Study, T. D. D. D., Twigg, S. R. F., & Suri, M.
- Affiliations
- Nottingham University Hospitals NHS Trust (GB)
- University of Exeter (GB)
- London North West Healthcare NHS Trust (GB)
- Birmingham Women's Hospital (GB)
- Wellcome Sanger Institute (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- Oslo University Hospital (NO)
- Leeds Teaching Hospitals NHS Trust (GB)
- Haukeland University Hospital (NO)
- Queen Elizabeth University Hospital (GB)
- University Hospital of Wales (GB)
- Western General Hospital (GB)
- Institute of Pathology and Genetics (BE)
- Liverpool Womens NHS Foundation Trust (GB)
- Manchester Academic Health Science Centre (GB)
- University Hospitals Bristol NHS Foundation Trust (GB)
- East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK
- Guy's Hospital (GB)
- University of Oxford (GB)
- Wellcome Trust Sanger Institute, Hinxton, UK
- Corresponding author
- Suri, Mohnish
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2017-10-11
- Volume
- 55
- Issue
- 1
- Pages
- 28-38
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC5749303
- OpenAlex
- W2763856094
- Cited by
- 43
- References
- 20
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 5
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Medical Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Health Innovation Challenge Fund
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- CDK13, kinase domain, developmental delay, intellectual disability, autism spectrum disorder, syndromic intellectual disability, missense mutations, splice site mutation, craniofacial dysmorphism, congenital heart disease, feeding difficulties, seizures, corpus callosum abnormalities, loss of function, dominant-negative mechanism
- MeSH terms
- Protein Domains, Adolescent, Child, Developmental Disabilities, Female, Heterozygote, Humans, Male, Intellectual Disability, Models, Molecular, Mutation, Syndrome, Thermodynamics, CDC2 Protein Kinase, Conserved Sequence, Mutation, Missense
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