“Genes that Prevent Congenital Heart Disease”

Doctor's Name: 
Patrick Jay, MD
Doctor's Name 2: 
Washington University School of Medicine

Congenital heart disease outcomes have improved dramatically in recent decades, but one can reasonably ask whether pediatric cardiology and cardiac surgery are nearing the limits of technical solutions.  Outcomes trends for complex heart defects appear to have leveled in the past decade. Still, congenital heart disease remains a leading cause of death among children, not to mention suffering for them and their families. New paradigms based upon novel scientific insights will be necessary to build upon past successes. In this regard, the last two decades have yielded tremendous progress in defining the genetic causes of congenital heart disease and their effects on cardiac development. What we have learned, however, makes a cure seem more distant than ever. The definitive solution is prevention, but the genetic mutations that have been discovered cannot be feasibly addressed by gene therapy or drugs for numerous ethical and technical reasons. 

Our research thus takes a fundamentally different approach. Rather than focusing on the causes, we ask why some individuals who share the same disease-causing mutation develop a structurally normal heart. We reason that they carry other genes that protect them. The genes are termed “modifiers” because their effect on the disease trait, i.e., normal or abnormal, are only manifest in the presence of the deleterious mutation. If the genetic modifiers that permit an embryonic heart to develop normally despite a serious mutation were understood, a drug might be developed that mimics a protective gene. The drug could be prescribed to expectant mothers to prevent a heart defect from forming in their child, just as folic acid is now to prevent neural tube defects. 

In a large, ongoing genetic analysis we discovered that modifier genes profoundly influence the development of very specific types of heart defects. Most interestingly, we observed that the predominant effect of modifier genes in a genetically heterogeneous population is to ensure normal cardiac development.  We used a mouse model that carries a mutation of the cardiac transcription factor Nkx2-5. Human NKX2-5 mutations were one of the first discovered to cause congenital heart disease. Nkx2-5 mutant animals develop the same heart defects observed in man, including simple septal defects, double outlet right ventricle, tetralogy of Fallot and common atrioventricular canal. Naturally occuring variants of the modifier genes in inbred mouse strains direct the developing Nkx2-5 mutant heart toward or away from very specific anatomic malformations. Modifier genes clearly can negate the effect of a deleterious mutation. 

Our lab seeks to define the genetic principles and the modifier genes that could lead to a solution for congenital heart disease. Through systematic crosses of the inbred strains, we have mapped the locations of the modifier genes to regions in the genome. Most all of these regions, commonly referred to as loci, do not contain known cardiac developmental genes, which indicates that we are in new genetic territory.

For one complex malformation, atrioventricular septal defect (AVSD or common atrioventricular canal), only two modifier genes may be involved. Just two protective versions or alleles of either gene in an Nkx2-5 mutant mouse appear to prevent this defect from forming. This is genetic proof of principle that a drug that mimics the protective allele of one of those genes could likewise be effective. Thus, one aim of this proposal is to characterize the genetic architecture of AVSD modifier genes, that is, how many there are, where they lie in the genome, and whether their effect is as strong as the preliminary data suggest. 

Once a genetic locus is found, the relevent gene in the region must be identified. This has historically been daunting, but new methods and technologies have dramatically accelerated gene discovery. Our lab developed bioinformatic methods to discover one gene that may influence VSD susceptibility in Nkx2-5 mutant animals. This gene was not at all suspected by cardiac developmental biologists. We propose in a second set of experiments to find other modifier genes by high-throughput DNA sequencing. The genes that lie within modifier loci will be highly suspect candidates for future investigation.

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