CDK13 – CDK13-related Syndromic Intellectual Disability

Heterozygous variants in CDK13 cause a syndromic form of syndromic intellectual disability, characterized by developmental delay, dysmorphic facial features, feeding problems, and structural brain and heart anomalies. Initial reports described 44 unrelated probands with de novo CDK13 variants, establishing the gene–disease link (PMID:30904094).

Patients typically present with global developmental delay, distinctive craniofacial gestalt (broad nasal bridge, hypertelorism), hypotonia, and feeding difficulties in infancy (HP:0008872). Structural heart defects (ventricular septal defects, atrioventricular septal defects) and brain malformations (ventriculomegaly, corpus callosum anomalies) occur in approximately one-third of cases. Baseline echocardiography and neuroimaging are recommended for all patients.

Inherited in an autosomal dominant manner, CDK13‐related disorder is usually caused by de novo missense or truncating variants. To date 46 affected individuals have been reported: 44 in the primary cohort (PMID:30904094) and a three-generation family comprising two affected individuals (mother and son) with a shared c.2149G>C (p.Gly717Arg) variant (PMID:35034425). Segregation analysis confirmed transmission in the familial case.

The variant spectrum is dominated by missense changes clustering within the kinase domain, with a smaller number of frameshift and nonsense alleles. One recurrent site, p.Asn842Ser, has been observed in multiple unrelated individuals, while truncating alleles are associated with milder features. A representative pathogenic change is c.3686C>T (p.Ser1229Leu), affecting the conserved activation segment of the kinase domain.

Mechanistic data suggest a dominant-negative effect of missense variants sequestering cyclin K into inactive complexes, whereas haploinsufficiency may underlie milder phenotypes. Functional validation in cellular assays remains to be performed to confirm these hypotheses.

Mouse models have provided moderate functional evidence: a hypomorphic Cdk13 allele leads to midfacial cleft and trigeminal nerve hypoplasia, while complete knockout causes embryonic lethality and craniofacial/heart defects mirroring the human phenotype (PMID:38511331; PMID:39556044).

Taken together, the genetic and experimental data support a strong clinical validity for CDK13 in syndromic intellectual disability. CDK13 variant testing is clinically useful for diagnosis, genetic counseling, and guiding multidisciplinary management.

References

• Advances in genetics • 2019 • CDK13-related disorder. PMID:30904094
• Molecular genetics & genomic medicine • 2022 • Genetic of preimplantation diagnosis of dysmorphic facial features and intellectual developmental disorder (CHDFIDD) without congenital heart defects. PMID:35034425
• Disease models & mechanisms • 2024 • Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered cranial neurogenesis. PMID:38511331
• Journal of anatomy • 2025 • Cyclin-dependent kinase 13 is indispensable for normal mouse heart development. PMID:39556044

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