Hypoplastic Left Heart Syndrome: Molecular Consequences of Transcription Factor Mutations

Hypoplastic Left Heart Syndrome (HLHS; MIM #241550) is a condition of congenital malformations of the left side of the heart. The left ventricle is typically underdeveloped and insufficient at supporting systemic circulation. The mitral valve may be improperly formed or closed completely and the aorta can be abnormally narrow. These abnormalities affect the heart's ability at pumping oxygenated blood to the body. Normally, the foramen ovale and patent ductus close at birth to permit blood to be oxygenated by the pulmonary circulation. However, in HLHS, the blood is pumped through the right ventricle pumping blood both to the lungs (via the pulmonary artery) and out to the body. Surgical intervention is required in order to correct these malformations. HLHS has been found to be more prevalent in males than females and 10% of patients are diagnosed with other birth defects. To date, it has been theorized that there is a genetic cause for HLHS; however, no known monogenic cause has been determined. Current research is investigating changes in genes known to be involved in cardiac development: TBX5, NKX2.5, GJA1, GATA4 , Hand1 and Hand2. TBX5 has been linked to Holt‐Oram Syndrome, which is a heart‐limb disease that has similar cardiac defects to HLHS. DNA from patients with HLHS will be analyzed to determine whether a genomic mutation is a cause of the cardiac defect. These results will be compared within a cohort of HLHS patients to determine if there is a genetic basis for their abnormal cardiovascular development.