Cardiac, Facial, And Digital Anomalies With Developmental Delay

A number sign (#) is used with this entry because of evidence that cardiac, facial, and digital anomalies with developmental delay (CAFDADD) is caused by heterozygous mutation in the TRAF7 gene (606692) on chromosome 16p13.

Clinical Features

Tokita et al. (2018) reported 7 unrelated patients with a similar multisystemic developmental disorder. Two patients were infants less than 4 weeks of age, 4 patients were children, and 1 was an adult (43 years). Five patients had abnormal prenatal ultrasound findings, including cystic hygroma, 2-vessel cord, and cardiac defects. Postnatal concerns included respiratory distress, poor feeding, hypotonia, and jaundice. The 5 older patients had delayed motor and speech development, including 1 patient (patient 7) who showed developmental regression in early childhood. Cardiac defects were variable and included pulmonary stenosis, patent ductus arteriosus, aortic coarctation, valvular defects, hypoplastic left heart, double outlet right ventricle, and conduction abnormalities. Dysmorphic facial features included multiple hair whorls or hairline abnormalities, ptosis, epicanthal folds, and low-set or dysplastic ears. Additional features included wide-spaced nipples, umbilical hernia, and distal anomalies of the hands and feet, such as creases, contractures, and overlapping digits. Two patients had seizures, 1 had possible absence seizures, 3 had tethered cord, and 3 patients had hearing loss, cortical blindness, and/or optic atrophy. Brain imaging showed enlarged ventricles in some patients; one patient had evidence of cortical gyral irregularities.

Molecular Genetics

In 7 unrelated patients with CAFDADD, Tokita et al. (2018) identified de novo heterozygous missense mutations in the TRAF7 gene (606692.0001-606692.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the ExAC or gnomAD databases. Four patients carried the same mutation (R655Q; 606692.0001). Two of the mutations occurred in WD40 domains and 2 in coiled-coil regions, both of which are functionally important. In vitro functional expression assays in HEK293 cells showed that the mutations resulted in variably decreased ERK1/ERK2 (MAPK3; 601795/MAPK1; 176948) phosphorylation after TNF-alpha (191160) stimulation compared to controls. Tokita et al. (2018) noted that Krumm et al. (2015) had identified a de novo heterozygous R655Q mutation in the TRAF7 gene in a patient with autism who was part of a cohort of 2,377 families with autism.