| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.12 | Cardioacrofacial dysplasia 1 | 619142 | Autosomal dominant | 3 | PRKACA | 601639 |
A number sign (#) is used with this entry because of evidence that cardioacrofacial dysplasia-1 (CAFD1) is caused by heterozygous mutation in the PRKACA gene (601639) on chromosome 19p13.
Cardioacrofacial dysplasia-1 (CAFD1) 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 (Palencia-Campos et al., 2020).
Genetic Heterogeneity of Cardioacrofacial Dysplasia
CAFD2 (619143) is caused by mutation in the PRKACB gene (176892) on chromosome 1p31.
Palencia-Campos et al. (2020) reported 3 unrelated families, from Egypt (family 1), Belgium (family 2), and Italy (family 3), in which 8 affected individuals exhibited postaxial polydactyly, primarily bilateral hexadactyly of the hands, although the feet were involved in some patients. Short long bones and brachydactyly were also observed, as well as long narrow thorax and short ribs in some patients. In addition, 6 patients had congenital cardiac septal defects, including atrial, ventricular, and atrioventricular septal defect, atrioventricular canal, single atrium, and single ventricle. One patient showed great vessel abnormalities, and 1 experienced pulmonary hypertension. Facial dysmorphisms included midface hypoplasia, short philtrum, and notched upper lip. Patients also displayed multiple oral frenula and dental anomalies, including diastema, hypodontia, and conical teeth. Clinical diagnoses included Weyers acrofacial dysostosis (WAD; 193530) and Ellis-Van Creveld syndrome (EVC; 225500).
The transmission pattern of CAFD1 in the families studied by Palencia-Campos et al. (2020) was consistent with autosomal dominant inheritance.
In 2 unrelated probands (P1 and P2) with cardioacrofacial dysplasia, who were negative for mutation in the EVC (604831) and EVC2 (607261) genes, Palencia-Campos et al. (2020) identified the same heterozygous missense mutation in the PRKACA gene (G137R; 601639.0002). The G137R variant was also found in heterozygosity in a third affected proband (P3). In P1, the variant was mosaic, with a variant allele fraction (VAF) of 0.28; his 2 affected offspring for whom DNA was available carried the variant in heterozygous state. The unaffected father of P2 was mosaic for G137R (VAF 0.16), but the variant was germline-transmitted in P2 (VAF 0.55) and her affected fetus (VAF 0.46). The mutation was found to have occurred de novo in P3.
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]