Genetics of Hypoplastic Left Heart Syndrome

Doctors D. Woodrow Benson from the Medical College of Wisconsin, Milwaukee, Lisa J. Martin from Cincinnati Children's Hospital Medical Center, and Cecilia W. Lo from the University of Pittsburgh School of Medicine recently published a paper on the genetics of hypoplastic left heart syndrome (HLHS). We asked one of our genetic researchers, Dr. Jeanne Theis, to give us an overall idea of what this paper means for those in the congenital heart disease (CHD) world.

Genetics of HLHS

HLHS is described as being a complex trait which means that the genetic cause is complicated. There are many factors that may be involved and, in order to fully understand the genetics, we have to take into account each one of them. Three terms commonly used to describe the genetics of HLHS are: genetically heterogeneous, variable expressivity and reduced penetrance. So what do we currently understand about the genetics of HLHS and how can we use this knowledge to help us understand more?

At this point in time, we know that HLHS is genetically heterogeneous. In other words, there isn’t a single gene that is associated with HLHS. There are many unique genes that are important during heart development and it is possible that a genetic variant in any one of those genes would be enough to lead to HLHS. While specific genes have been found to be linked to HLHS, they are identified in a very small subset of individuals.

Variable expressivity is a second term that is often used when describing HLHS. This means that the same genetic variant may cause many different types of congenital heart disease (CHD), including HLHS. While it is uncommon to have two family members with HLHS, multiple papers have been published discussing a strong familial clustering of HLHS with other CHDs. Recently, Dr. Angela Kelle published a study in the American Journal of Cardiology which found when studying family members of 52 patients with HLHS, 11% were found to have a CHD. While the CHDs are typically not as severe as HLHS from a developmental perspective, it makes sense that they may be linked at the level of the specific genetic variant. The big question as to why a single genetic variant may cause HLHS in one patient and a bicuspid aortic valve in their sibling is unknown and may be due to other genetic variants or possible environmental factors.

Reduced penetrance is a perplexing factor in the world of human genetics. This suggests that one family member may carry the same variant that is thought to cause HLHS in another family member, but that individual appears to have no CHD himself. While there may be a variant that drives HLHS during the early stages of heart development, there are likely other factors involved in the occurrence of this complex trait.

In an effort to take into account all of these factors, our program sequences the entire genome of all study participants (individuals with HLHS, mothers, fathers, siblings and any additional family members known to have a CHD). With this approach, we are able to analyze the millions of variants in each individual’s genetic blueprint and are not required to focus on a specific subset of genes. While we do look for rare variants in genes among individuals with HLHS, we also focus on the genomic sequence of each family unit. If we know that a mother has a bicuspid aortic valve, we will look at those variants that she shares with her child who has HLHS. The sequencing and annotation of variants within a genome is no longer the limiting step it was in the past. Our current challenge is to identify the one, two or five variants that are important for HLHS from the millions of variants within a single genome.

For questions related to our research or how to get involved, please contact our program at HLHS@mayo.edu.

The Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome (HLHS) is a collaborative network of specialists bonded by the vision of delaying or preventing heart failure for individuals affected by congenital heart defects including HLHS. The specialized team is addressing the various aspects of these defects by using research and clinical strategies ranging from basic science to diagnostic imaging to regenerative therapies.