A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects-8 with or without heterotaxy (CHTD8) is caused by heterozygous mutation in the SMAD2 gene (601366) on chromosome 18q21.

Multiple types of congenital heart defects-8 (CHTD8) is characterized by cardiac septal defects, double-outlet right ventricle, unbalanced complete atrioventricular canal, and valvular anomalies, as well as vascular anomalies including dextroposition of the great arteries, anomalous pulmonary venous return, and superior vena cava to left atrium defect. Patients may also exhibit laterality defects, including dextrocardia, atrial isomerism, dextrogastria, left-sided gallbladder, and intestinal malrotation (Zaidi et al., 2013; Granadillo et al., 2018).

Zaidi et al. (2013) reported 2 unrelated patients who had complex congenital heart disease with heterotaxy and mutation in the SMAD2 gene. Patient 1-02020 had dextrocardia, unbalanced complete atrioventricular canal (CAVC), pulmonary stenosis, double-outlet right ventricle (DORV), dextroposition of the great arteries (DTGA), and atrial septal defect (ASD), as well as asplenia. Height and weight were at the 95th and 10th percentile, respectively, and neurologic development was normal. Patient 1-02621 had dextrocardia, unbalanced right-dominant CAVC, pulmonary stenosis, DORV, superior vena cava to left atrium defect, and partial anomalous pulmonary venous return (APVR), as well as abnormal nose, foot syndactyly, and gut malrotation. Height and weight were at the 50th percentile for each; information on neurodevelopment was not available.

Using GeneMatcher, Granadillo et al. (2018) ascertained 3 individuals, a 2-year-old girl (patient 1), a 10-year-old girl (patient 2), and a female fetus (patient 3), who had complex congenital heart defects with other congenital anomalies and mutation in the SMAD2 gene. All 3 had ASD and ventricular septal defect (VSD); additional defects included DORV and valvular anomalies in patients 1 and 2, DTGA in patient 1, and unbalanced CAVC, APVR, and hypoplastic left ventricle in the fetus. The fetus also exhibited laterality defects, including dextrocardia, atrial isomerism, dextrogastria, and left-sided gallbladder. Other features in patients 1 and 2 included short stature, poor weight gain, developmental delay, and seizures, as well as dysmorphic features including midface hypoplasia, high-arched palate, micrognathia, and dental crowding.

The heterozygous mutations in the SMAD2 gene that were identified by Zaidi et al. (2013) and Granadillo et al. (2018) in patients with congenital heart defects occurred de novo.

From a cohort of 362 parent-offspring trios in which a child had severe congenital heart disease but no first-degree relative with structural heart disease, Zaidi et al. (2013) identified 2 unrelated patients with congenital heart defects and heterotaxy who were heterozygous for de novo mutations in the SMAD2 gene: patient 1-02020 had a splice site variant (601366.0001) and patient 1-02621 had a missense variant (W244C; 601366.0002).

In 3 patients with complex congenital heart defects, including 1 with heterotaxy, Granadillo et al. (2018) identified heterozygous mutations in the SMAD2 gene: a nonsense mutation (E159X; 601366.0007) in patient 1, a missense mutation (C312S; 601366.0008) in patient 2, and a splice site mutation (601366.0009) in patient 3. None of the mutations were found in public variant databases. In patients 2 and 3, the mutations were shown to have occurred de novo; the father of patient 1 was unavailable for testing. In patient 1, who also exhibited a single central incisor, analysis of a holoprosencephaly panel revealed a known HPE-associated variant (see HPE4, 142946) in the TGIF1 gene (Q107L; 602630.0006).