Congenital Heart Defects, Multiple Types, 6

A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects (CHTD6) are caused by heterozygous mutation in the GDF1 gene (602880) on chromosome 19p13.

Description

Multiple types of congenital heart defects are associated with mutation in the GDF1 gene, including tetralogy of fallot (TOF), transposition of the great arteries (TGA), double-outlet right ventricle (DORV), total anomalous pulmonary venous return (TAPVR), pulmonary stenosis or atresia, atrioventricular canal, ventricular septal defect (VSD), and hypoplastic left or right ventricle (Jin et al., 2017).

For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.

Clinical Features

From a cohort of 375 unrelated individuals with a wide spectrum of congenital cardiovascular malformations, Karkera et al. (2007) identified 8 patients with mutations in the GDF1 gene. Diagnoses reported for the patients included TOF in 3 patients and TGA in 2 patients. Atrioventricular canal was reported in 2 patients, 1 of whom was also diagnosed with cleft mitral valve, left superior vena cava to coronary sinus, and coarctation of the aorta, whereas the other was diagnosed with left pulmonary artery stenosis, hypoplastic left lung and pulmonary veins, as well as small secundum atrial septal defect (ASD) and trisomy 21. In addition, DORV with left pulmonary artery stenosis was reported in 1 patient.

From a cohort of 2,871 probands with congenital heart disease, Jin et al. (2017) identified 10 probands with the same homozygous mutation in the GDF1 gene. All 10 patients were reported to have conotruncal cardiac defects and heterotaxy, with diagnoses that included TOF, TGA, DORV, TAPVR, pulmonary stenosis or atresia, left superior vena cava to coronary sinus, coronary artery anomalies, right aortic arch, left ventricular outflow tract obstruction, hypoplastic left or right ventricle, and single ventricle. In addition, 2 patients were reported to have inguinal hernias, and 3 had unspecified neurodevelopmental disorders (NDDs); in 2 patients the presence or absence of NDDs was unknown.

Molecular Genetics

Karkera et al. (2007) screened the GDF1 gene in 375 unrelated individuals with a wide spectrum of congenital cardiovascular malformations, a group of 225 normal controls, and 198 patients with holoprosencephaly (HPE; see 236100). Eight heterozygous mutations were identified in 8 patients from the cardiovascular malformation group (see, e.g., 602880.0001-602880.0003). No mutations were found in the controls or patients with HPE. Functional analysis in zebrafish indicated that the mutations represented hypomorphic or loss-of-function alleles. The authors concluded that the phenotypes observed were consistent with a model of disturbed left-right patterning, with incomplete establishment of left-sided identity.

In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, Jin et al. (2017) performed whole-exome sequencing and identified 10 probands who were all homozygous for the same missense mutation in the GDF1 gene (M364T; 602880.0006). Principal component analysis of the WES genotypes showed that all M364T homozygotes clustered with Ashkenazim and exhibited a shared haplotype, the length of which varied widely, indicating remote shared ancestry that was inferred to have occurred 50 generations earlier.