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.

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.

Bostwick et al. (2017) reported 9 patients with CHDFIDD recruited from clinical and research exome laboratory sequencing cohorts, to minimize ascertainment bias. Two-thirds of their patients had congenital heart defects, confirming that this feature is a prominent component, but not seen in all patients with the syndrome. The authors reviewed clinical features on all 29 patients reported to that time. Distinctive facial features included hypertelorism, epicanthal folds, highly-arched eyebrows, wide nasal bridge, short columella, thin upper lip, and abnormal ears. Strabismus (69%), abnormal tone (69%), spasticity (15%) and musculoskeletal abnormalities (62%) were commonly seen. All patients had gross motor and language delay, with intellectual impairment ranging from mild to severe. Several patients had poor weight gain or short stature, and 4 patients had microcephaly. Central nervous abnormalities were seen in 10 of 11 patients on whom MRI was performed. Renal and spinal abnormalities were also seen.

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 variably impaired intellectual development, 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.

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.

In 9 patients with CHDFIDD, Bostwick et al. (2017) identified heterozygous mutations in the CDK13 gene. Two patients had novel CDK13 missense mutations (e.g., N842D; 603309.0005), whereas the other 7 had the previously identified recurrent variant N842S (603309.0001). The authors also reviewed 20 previously reported patients with CDK13 pathogenic variants. Of the total of 29 patients with CDK13 pathogenic variants, mutations were de novo in 27 and of unknown inheritance in 2 due to unavailability of parental samples. All variants were missense mutations predicted to impact the protein kinase domain, with clustering in the ATP-binding and magnesium binding sites. More than half (15/29) affected asparagine-842 (14 patients with N842S and 1 patient with N842D), suggesting its importance in magnesium binding. The authors noted that the clustering of missense mutations within a single protein domain and the lack of loss-of-function variants is consistent with a possible gain-of-function mechanism.

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.