Congenital heart defects (CHDs) are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. Only one causative gene, NKX2-5, has been identified through genetic linkage analysis of pedigrees with non-syndromic CHDs. Here, we show that isolated cardiac septal defects in a large pedigree were linked to chromosome 8p22-23. A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals. This mutation resulted in diminished DNA-binding affinity and transcriptional activity of Gata4. Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects. In a second family, we identified a frame-shift mutation of GATA4 (E359del) that was transcriptionally inactive and segregated with cardiac septal defects. These results implicate GATA4 as a genetic cause of human cardiac septal defects, perhaps through its interaction with TBX5.

GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, 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 were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

/pdf/contribution-of-rare-inherited-and-de-novo-variants-in-2-871-3gsrwd2z93.pdf

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

Congenital heart disease is the leading cause of infant morbidity in the Western world, but only in the past ten years has its aetiology been understood. Recent studies have uncovered the genetic basis for some common forms of the disease and provide new insight into how the heart develops and how dysregulation of heart development leads to disease.

The developmental genetics of congenital heart disease

https://gladstone.org/u/dsrivastava/Articles/Srivastava%20Cell%202006.pdf

Making or Breaking the Heart: From Lineage Determination to Morphogenesis

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus

Editor—Holt-Oram syndrome (HOS) is a developmental disorder characterised by malformations of the radial ray of the forelimb and by congenital heart disease.1 The syndrome shows a marked variability in phenotype, with radial ray defects ranging from minor thumb abnormality through to severe reduction defect or phocomelia. The cardiac manifestations of HOS are similarly varied, and patients can present with a variety of structural heart abnormalities, atrial septal defects (ASDs) and ventricular septal defects (VSDs) being the most common, or conduction defects evident on ECG profiles. Previous studies have shown no correlation between the severity of a patient's cardiac and skeletal abnormalities.2 Intrafamilial variation can be wide.

HOS shows autosomal dominant inheritance and mutations in the T box transcription factor gene ( TBX5 ) have been shown previously to be responsible for this disorder.3 4There is also evidence for genetic heterogeneity.5 The mechanism by which mutations in TBX5 cause a dominant phenotype is not understood at present, and it is anticipated that knowledge of the type of mutations causing HOS may shed light on this. Knowledge of a large number of mutations and the relation of a person's genotype to phenotype is also useful for genetic counselling. In the face of a growing demand for a molecular diagnostic test for HOS, it is also helpful to have a quantitative estimate of the ability of current methods to detect mutations in TBX5 .

Twenty five cases with a clinical diagnosis of Holt-Oram syndrome have been tested for this study, bringing to 47 the total number of cases studied by us. Minimal diagnostic criteria were as described previously2: bilateral radial ray defect, plus either cardiac abnormality or family history of cardiac abnormality. Cases were referred by a variety of clinicians and underwent full clinical assessment including …

https://jmg.bmj.com/content/jmedgenet/37/10/785.full.pdf

The mutation spectrum in Holt-Oram syndrome

Ching, Y. H. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nature Genet. 37, 423-428

Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in α-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.

Mutation in myosin heavy chain 6 causes atrial septal defect.

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The mutation spectrum in Holt-Oram syndrome

Ching, Y. H. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nature Genet. 37, 423-428

Mutation in myosin heavy chain 6 causes atrial septal defect.