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

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 transmitted 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 19 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

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2%of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator ofmRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients

De novo mutations in congenital heart disease with neurodevelopmental and other birth defects

Congenital heart disease (CHD) patients have increased prevalence of extra-cardiac congenital anomalies (CA) and risk of neurodevelopmental disabilities (NDD). Exome sequencing of 1,213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD and CA but only 2% with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, an mRNA splice regulator. Genes mutated in other cohorts ascertained for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients

Screening for sudden cardiac death in the young: report from a national heart, lung, and blood institute working group.

The debate over cardiovascular screening to prevent sudden cardiac death in the young (SCDY) has fervent and well-intentioned supporters on both sides.However, this debate will continue unresolved until additional,compelling evidence is provided that either supports orrefutes the utility of screening for SCDY. In an effort to provide direction to determine what type of evidence is necessary and the best methodology to obtain such evidence, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group meeting in April 2010 in Bethesda, MD. The charge of the Working Group was to develop a research agenda and identify resources to evaluate whether screening for SCDY would effectively reduce sudden cardiac death and add overall healthcare value, where value was defined as improved clinical outcomes with an acceptable cost-benefit ratio. The Working Group consisted of experts in pediatric cardiology and electrophysiology, adult cardiology, epidemiology, biostatistics, sports medicine, child psychiatry, health economics, ethics, oncology screening, and newborn screening