Hypoplastic left heart syndrome (HLHS) is caused primarily by genetic factors, and this new understanding of cause may direct research to identify the genes involved, understand the flaws in cardiac development, and develop better treatments, according to an article in the October 16 issue of the Journal of the American College of Cardiology.

The study, conducted at Cincinnati Children’s Hospital Medical Center, is the first to show high heritability and likely genetic underpinnings the syndrome.

“Our study demonstrates that HLHS has high heritability, suggesting it is caused almost entirely by genetic effects instead of environmental factors, and that families with a child with HLHS carry a significant recurrence risk of HLHS or related heart defects. This should be considered by physicians when counseling parents to ensure they are aware of potential risks,” said Robert B. Hinton, Jr., MD, a researcher at Cincinnati Children’s and the study’s lead author.

The syndrome is rare, occurring in about 2 of every 10,000 children born, Hinton said. Among affected infants, approximately 20 percent die during the first months of life. Despite significant advances in diagnosis and therapy, the condition remains challenging to treat and the specific causes remain unknown. Babies can survive by undergoing a series of three complex operations after birth or receiving a heart transplant.

The study at Cincinnati Children’s included 38 family-based test groups with a history of the syndrome. Researchers found that 55 percent of families had one or more blood relative with the syndrome or an associated heart defect. Of 193 blood relatives evaluated between the ages of 3 days and 74 years, 21.4 percent had the syndrome or associated heart defects.

In families where one child already was affected, the risk of recurrence in a sibling was 8 percent while the risk of a sibling having an associated cardiovascular defect was 22 percent. In families where a child and one parent had the syndrome, the recurrence risk increased dramatically to 21 percent for the syndrome and 25 percent for an associated defect.

All participants were evaluated using echocardiography to determine specific phenotype. During those examinations researchers diagnosed 12 new cases of associated defects among relatives of patients.

Researchers recommend further studies to pinpoint specific genes responsible for the condition. Finding the genetic basis could have significant implications for treating children with the disease, said D. Woodrow Benson, MD, PhD, director of Cardiovascular Genetics at Cincinnati Children’s and the study’s senior author. This includes identifying possible interventions during fetal life (such as catheter-based procedures), the most appropriate postoperative drug therapies for individual children and determining the potential risks for failure of the right ventricle.

“By using family-based linkage analysis, where specific genetic traits are mapped, it should be possible to identify the genes that cause the disease,” Benson said. “Once we know what genes are involved we can study how the disease developments, which may lead to new treatment approaches.”

Earlier studies in animals indicate the syndrome may develop because of embryonic alterations in blood flow, such as a premature narrowing of the aortic valve and foramen ovale. Other studies have pointed to the role of certain genes (TBX5 and IRX1) in the formation of defective heart chambers with distinct shapes, functionality and molecular structure. Based on analysis of how these genes function, scientists hypothesize that the syndrome may result from a primary defect in the growth of muscle tissue during the heart’s development.

“Currently there are no experimental models to clarify the relative contributions of these two hypotheses to the development of the syndrome,” Hinton said. “An important step forward in this research will be to understand the degree to which these hypothetical causes actually contribute to the condition.”