New genes implicated in deadly heart defect

Scientists from Sanford Burnham Prebys have made progress in understanding hypoplastic left heart syndrome (HLHS), a rare and life-threatening heart disease in infants, by identifying new genes associated with the condition. The findings, published in the journal eLife, represent a step forward in unraveling the biology of this complex disease.

HLHS occurs when the left side of the heart, specifically the left ventricle, is underdeveloped and unable to effectively pump oxygenated blood throughout the body. It is estimated that approximately 1,025 babies in the United States are born with HLHS each year, accounting for 2-4% of all congenital heart defects. Although rare, HLHS is highly dangerous and typically requires multiple open-heart surgeries for survival.

While the role of genetics in HLHS is well-established, the specific genes involved have remained elusive. To identify genes contributing to HLHS, the researchers conducted genome sequencing on 183 individuals with HLHS and their parents, including a family in which the parents shared genetic relatedness. This particular family enabled the researchers to focus their search on a select set of key genes.

Georg Vogler, Ph.D., a research assistant professor at Sanford Burnham Prebys and co-senior author of the study, explains, “If both parents pass down a gene variant that can cause problems, then the effect of that gene variant is accentuated in the child. Because of this effect, this family gave us a unique opportunity to look for new genes that drive HLHS that may not be as apparent in other families.”

To investigate whether the identified genes played a role in HLHS, the researchers conducted genetic experiments on fruit flies, whose hearts possess genes similar to those found in human hearts. They discovered that disrupting the activity of these genes in fruit flies impeded the contraction of the heart, resulting in significant heart defects.

Rolf Bodmer, Ph.D., director of the Center for Genetic Disorders and Aging Research at Sanford Burnham Prebys and senior author of the study, offers a hypothesis to explain the findings: “This could lead to the types of abnormalities seen in HLHS.”

While the study successfully identified genes associated with HLHS, the researchers caution that it is unlikely a single gene will be implicated in the disease in all cases. HLHS is influenced by a combination of genetic and environmental factors. Nonetheless, shedding light on these factors provides valuable insights for potential prevention and treatment strategies.

Bodmer suggests that increasing the activity of one of these genes may strengthen the heart and reduce the risk of heart complications in HLHS survivors. Further research is necessary to fully comprehend how these genes contribute to heart defects.

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