| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p31.1 | Cardioacrofacial dysplasia 2 | 619143 | Autosomal dominant; Somatic mosaicism | 3 | PRKACB | 176892 |
A number sign (#) is used with this entry because of evidence that cardioacrofacial dysplasia-2 (CAFD2) is caused by heterozygous mutation in the PRKACB gene (176892) on chromosome 1p31.
Cardioacrofacial dysplasia-2 (CAFD2) is characterized by congenital cardiac defects, primarily common atrium or atrioventricular septal defect; limb anomalies, including short limbs, brachydactyly, and postaxial polydactyly; and dysmorphic facial features. Developmental delay of variable severity has also been observed (Palencia-Campos et al., 2020).
For a discussion of genetic heterogeneity of CAFD, see CAFD1 (619142).
Palencia-Campos et al. (2020) reported 4 unrelated probands from Denmark (P4), France (P5 and P6), and Australia (P7) who exhibited congenital cardiac defects, including single atrium in 3 and atrioventricular septal defect in 1. Three patients had valvular defects, and 1 had persistent left superior vena cava draining into the coronary sinus. In addition, all showed postaxial polydactyly of the hands, with 3 also having involvement of the feet. Long narrow thorax was present in 2 of the patients, who also showed short broad hands and feet; other variable bone anomalies were also observed in the 4 patients. Facial dysmorphisms included long face with prominent nose and chin, oral frenula, and dental anomalies, including hypodontia, supernumerary teeth, and conical teeth. Developmental delay was observed in 3 of the 4 patients (P4, P6, and P7), with severe intellectual disability in 1 (P7), who also showed autistic features and focal seizures. Two of the patients (P4 and P5) were clinically diagnosed with Ellis-Van Creveld syndrome (EVC; 225500).
The transmission pattern of CAFD2 in the families studied by Palencia-Campos et al. (2020) was consistent with autosomal dominant inheritance.
In 4 unrelated probands with CAFD2, Palencia-Campos et al. (2020) identified heterozygosity for de novo missense mutations in the PRKACB gene (176892.0001-176892.0004) that were not found in the gnomAD database. In 1 patient (P5), the mutation was present at a variant allele fraction (VAF) of 0.32, and electropherograms confirmed mosaicism.
Palencia-Campos, A., Aoto, P. C., Machal, E. M. F., Rivera-Barahona, A., Soto-Bielicka, P., Bertinetti, D., Baker, B., Vu, L., Piceci-Sparascio, F., Torrente, I., Boudin, E., Peeters, S., and 30 others. Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome. Am. J. Hum. Genet. 107: 977-988, 2020. [PubMed: 33058759] [Full Text: https://doi.org/10.1016/j.ajhg.2020.09.005]