Study Finds Possible Genetic Mutation Cause for Hypoplastic Left Heart Syndrome (HLHS)

Here at the Todd and Karen Wanek Family Program for HLHS, our goal is to find a cause to determine a cure. Our researchers have been working tirelessly to find the cause using a wide range of methods looking from imaging, or the study of images, to genetics, the study of genes. Current understanding of the molecular basis of HLHS is limited.

One of our researchers, Dr. Jeanne Theis, recently had her paper entitled, “Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome” published in Human Genetics. This research study is important because it identifies HLHS-associated gene mutations in a child with HLHS. It is also the first paper in the program to describe the impact of gene mutations using patient-specific pluripotent stem cells. Pluripotent stem cells can be converted into beating heart cells and assessment may enhance the understanding of how gene mutations lead to HLHS.

Researchers were able to identify HLHS-associated mutations in a single gene by looking at the entire genome of each family member. After filtering through millions of variants, they were able to hone in on mutations in the NOTCH1 gene. While they were not looking for a specific gene, NOTCH1 stood out due to an important role it plays in heart development. The study went on to look at stem cells from this patient with HLHS as well as the mother and father. Converting these stem cells to beating heart cells allowed researchers to determine the negative impact the identified NOTCH1 mutations had on heart development. Ultimately, the patient stem cells supported the genetic discovery of NOTCH1 mutations in HLHS.

In summary, the overall findings of the study implicate gene changes as a possible cause of HLHS. The HLHS patient studied has two mutations in the same gene, NOTCH1, whereas the parents each have a single mutation that they pass to the child with HLHS. In the study, one of the mutations in NOTCH1 comes from the mother who has a less severe congenital heart defect. Two mutations in NOTCH1 in the HLHS child compromise both copies of the gene and are associated with the severe congenital heart defect. A single copy of mutated NOTCH1 is not necessarily good news as it may still lead to a less severe congenital heart defect. Studies such as this one are leading us on the right path in our understanding of HLHS and bring the hope of more advancements in the future.

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.