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Behind the bench... with Dr. Richard Lifton, Yale University

Gary H. Gibbons, M.D. - June 13, 2013

New research sheds light on causes of congenital heart disease

Head shot of a man in a dress shirt and tie
Each year, approximately 40,000 children are born with congenital heart disease (CHD), the most common birth defect. While research advances have allowed children born with CHD to live longer, healthier lives, those who survive past infancy often face long-term disabilities and shorter-than-average lifespans. The complicated nature of this disease historically has meant that we know little about the fundamental causes. Our limited knowledge has meant we can try our best to treat it through complicated surgeries and post-surgery therapies, but can do little, if anything, to prevent it.


Now, thanks to the team of scientists in the NHLBI-funded Pediatric Cardiac Genomics Consortium (PCGC), researchers are beginning to gain new knowledge about potential causes of this condition. In a study led by Dr. Richard Lifton from Yale University, these researchers recently published a paper in Nature that reported on the findings from the first large-scale sequencing analysis of congenital heart disease. The analysis, which was done using state-of-the-art whole exome sequencing and genome mapping techniques, found that spontaneous (de novo) mutations contribute to the pathogenesis of severe CHD. Strikingly, many of these mutations affect a specific biological pathway that is critical to aspects of human development, including the brain and heart. This research also furthered more recent revelations that histone proteins, once seen as "inert packing material," are, in fact, involved in regulating genes. This provocative finding brings us one step closer to understanding how pathogenesis actually works at the molecular level.


The discoveries from this research reinforce the importance of new sequencing and mapping technologies in helping move medical research to the next level of discovery. They also raise questions about what role the in-utero environment may play in causing mutations and how we may be able to use diet or other aspects of the environment to help prevent them. And, because mutations explained pathogenesis in only 10 percent of the patients, this study also lets us know that there are another 90 percent of the cases where the cause of CHD is still unknown. The challenging questions that result from this study will help shape the direction of future research. And the answers we have in hand now may help change how medicine currently is practiced.

This study also plays an important role in reinforcing the power of research consortia, which allow for clinical trials and data collection on a level that could never happen by a solo researcher. Since its inception in 2010, the Pediatric Cardiac Genomics Consortium has recruited 6,000 patients who have congenital heart disease.

Changing Gears

Dr. Lifton's work with adults and genomics is equally intriguing. Besides tackling the most common birth defect, he's exploring the genetics basis of another prevalent condition worldwide—hypertension. Specifically, he's investigating hypertension and the underlying biology of tumors of the adrenal gland. These specific tumors, which are present in 5-10 percent of patients with hypertension, secrete the hormone aldosterone, which is the cause of hypertension in these patients. Dr. Lifton's findings—that 40 percent of these tumors are caused by mutations in a single potassium channel—may one day lead to new diagnostics and therapeutics.

Dr. Lifton's research portfolio is a testament to the critical role that genetics will continue to play as the medical community seeks to find cures and treatments for diseases across the heart, lung, and blood space (and beyond).

Dr. Lifton's career to date shows how far we've come in the past 30-plus years—and how much further we can go. There are many more exciting contributions Dr. Lifton and his PCGC colleagues are poised to make in this exciting field of research.


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