Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.

Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes

“…While more commonly associated with cardiomyopathy (dilated, hypertrophic, or restrictive), mutations in genes encoding for components of the cardiac sarcomere, the basic contractile unit of striated muscle, have been determined to be responsible for familial and sporadic CHD. Examples include mutations in MYH7 (β myosin heavy chain) in individuals with Ebstein anomaly of the tricuspid valve, in ACTC1 (cardiac α actin) in familial ASD, and in MYH6 (α myosin heavy chain 6) in autosomal dominant familial ASD and sporadic cases of more complex CHD, including Shone complex and HLHS . There is mounting evidence that genetic variation in sarcomeric genes can concurrently cause CHD and affect ventricular function.…”

“…Similarly, multiple studies have shown that CHD patients with sarcomeric mutations have differential clinical outcomes, including reduced ventricular performance and transplant‐free survival. In a recent study of 2645 parent‐offspring trios and 226 singletons who underwent exome sequencing by the PCGC, 7 had recessive genotypes involving MYH6 . Five of the 7 had left ventricular outflow tract obstructive lesions, including 4 with Shone complex (which is characterized by mitral and aortic valve abnormalities).…”

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

“…Common variant genome-wide association studies (GWAS) have been particularly successful in adult-onset disorders and most loci discovered are in the noncoding genome 7 . In early-onset disorders with reduced fecundity, including autism spectrum disorder (ASD) 8 , discovery has been largely driven by the identification of extremely rare, gene-disrupting, de novo mutations that exert considerable risk 4,5,9 .…”

Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease

“…CHD can be divided into nonsyndromic phenotypes, including gene mutations, and syndromic phenotypes, including chromosomal abnormalities, such as Down's syndrome, Edwards syndrome, and Patau syndrome. Only about one-third of CHD cases have been described as clear genetic or chromosomal abnormality cases [2,3]. The causes of CHD are complex and involve interaction among the environment, genetics, and epigenetics.…”