Congenital Heart Defects, Dysmorphic Facial Features, And Intellectual Developmental Disorder

A number sign (#) is used with this entry because of evidence that congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD) is caused by heterozygous mutation in the CDK13 gene (603309) on chromosome 7p14.

Clinical Features

Sifrim et al. (2016) reported 7 unrelated children, ranging in age from infancy to 12 years, with a syndrome associated with atrial and/or ventricular septal congenital heart defects. Two patients had pulmonary valve abnormalities. Each patient had a recognizable facial gestalt characterized by hypertelorism, upslanted palpebral fissures, epicanthal folds, ptosis, strabismus, posteriorly rotated ears, thin upper lip, and small mouth. All had global developmental delay with significantly delayed walking and speech acquisition and intellectual disability. Four patients had seizures. Three patients had mild microcephaly, and 4 had feeding difficulties. Brain imaging showed agenesis of the corpus callosum in 3 patients, aplasia of the inferior half of the cerebellar vermis and small cerebral cortex in 1, and periventricular leukomalacia in another. More variable features included clinodactyly and/or camptodactyly of the fingers, hypotonia, and joint hypermobility. One patient had spasticity.

Hamilton et al. (2018) reported 9 additional patients, ranging in age from 3.5 to 16 years, with CHDFIDD. The patients had global developmental delay and variable intellectual disability, often with learning disabilities and autistic features. All but one had significant feeding difficulties from infancy, although only some had poor growth. All shared a common craniofacial gestalt including short upslanting palpebral fissures, telecanthus or hypertelorism, epicanthal folds, small mouth with thin upper lip, low-set or posteriorly rotated ears, and curly hair. Most had digital anomalies, including clinodactyly and prominent fetal pads, 2 had structural cardiac anomalies, and 1 had seizures.

Molecular Genetics

In 7 unrelated children with CHDFIDD, Sifrim et al. (2016) identified heterozygous missense mutations in the CDK13 gene (603309.0001-603309.0004). Six of the mutations were proven to have occurred de novo; paternal DNA from the seventh patient was not available, but his mother did not carry the variant. Four patients carried the same mutation (N842S; 603309.0001). All mutations occurred in the highly conserved protein kinase domain, and molecular modeling predicted that the mutations would impair ATP binding, binding of the magnesium ion essential for enzyme activity, or interactions with cyclin K (603544). Six of the patients were ascertained from a cohort of 518 trios in which a child with syndromic congenital heart defects underwent exome sequencing; the seventh patient was 1 of 86 singleton cases. Statistical analysis indicated that de novo missense mutations in the CDK13 gene were significantly enriched in patients compared to those expected under a null mutational model (p = 2.26 x 10(-12), Bonferroni-corrected p = 0.05). Functional studies of the variants and studies of patient cells were not performed.

Hamilton et al. (2018) reported 9 additional unrelated patients with CHDFIDD associated with de novo heterozygous mutations in the CDK13 gene that were identified by whole-exome sequencing (see, e.g., 603309.0001-603309.0002; 603309.0005-603309.0006). Aside from 1 patient with a splice site mutation, all mutations were missense substitutions affecting highly conserved residues. All mutations, including the splice site mutation, occurred within the protein kinase domain, and none were found in the gnomAD database. Molecular modeling and structural analysis indicated that all the missense variants would cause changes to bonding and/or structure that would likely lead to significant loss of catalytic activity. Hamilton et al. (2018) postulated a dominant-negative effect wherein the mutant missense variants would sequester cyclin K into inactive complexes or compete with active complexes for binding to substrates. In vitro functional expression studies of the variants were not performed.