Cardiovascular Genetics: Paying Individual Dividends

AS THE ULTIMATE BIG-DATA EFFORT IN BIOLOGY, THE HUMAN GENOME PROJECT commandeered scientific and societal resources in exchange for the promise of better health care. We are beginning to realize a return on our investment—and cardiovascular medicine is a trendsetter in reaping these rewards.

Now that massively parallel DNA sequencing yields large amounts of affordable DNA sequence, we can harness this genetic information for individual medical decision-making (1). At the core of this revolution are rare “private” DNA variants (2). Usually found in less than 1% of the population, rare variants are evolutionarily younger and so have faced less selection than have common variants, which have reached population equilibrium. Rare variants have the capacity to be genetically more potent, with more profound effects on phenotype.

Nevertheless, the nature of this individualized genetic information challenges the practices of conventional population-based genetic research, which emphasizes common genetic variants and their role in causing human disease. T e average human has ~4 million DNA nucleotides that differ from those of the reference human genome sequence. In each individual genome, at least 100,000 of these DNA variants are rare. T ese uncommon genetic variants can determine disease susceptibility, protect against illness, or may be relatively neutral. Studying rare genetic variation requires new methods because by their nature, such variants or combinations of variants may occur only once in the population.

Despite the scientific hurdles, patients with cardiovascular disease are already benefiting from genetic advances. T ese ailments—heart failure, cardiomyopathy, congenital heart disease, arrhythmias, and vascular diseases—tend to be highly heritable. Some are Mendelian single-gene disorders: hypertrophic cardiomyopathy, long QT syndrome, Marfan syndrome, and Loeys Dietz syndrome. Others, such as dilated cardiomyopathy and congenital heart disease, have a major genetic contribution but with a less-than-clear inheritance pattern. For example, dilated cardiomyopathy and right ventricular cardiomyopathy can be enriched in successive generations within a family but appear at less than the 50% rate expected for dominant inheritance. Researchers have identified uncommon and rare variants in an increasing number of genes linked to dilated cardiomyopathy. To diagnose the genetic defect causing dilated cardiomyopathy in a single individual, 50 to 80 different genes are sequenced simultaneously to find the disease-causing rare variant or variants. Use of this “gene panel” testing has expanded rapidly. Just 5 years ago, cardiomyopathy gene panels comprised only one to five genes, on average. Adding even more genes to the testing panels has improved the odds of diagnosing the variant responsible for cardiomyopathy. Genetic diagnosis is rapidly being woven into treatment plans to take advantage of the fact that certain variants indicate a patient’s risk of developing irregular heart rhythms or more rapid disease progression.

In the near future, genetic testing will sample the entire genome (3), with the goal of increasing sensitivity without increasing cost. Whole-exome and whole-genome sequencing can already be applied for less than the cost of gene panels, although to be informative, such approaches need to probe the genome with sufficient depth to ensure good coverage. Such broad-based testing yields a plethora of genetic variants, and so we must continue to improve our analytical tools that identify the true pathogenic genes and variants. Already, gene panel testing often returns more than one potential causal mutation, leaving it to the clinician and counselor to determine the primary “driver” mutations and assess whether other variants play a modifier role.

Cardiovascular genetics is poised to expand beyond specialty practices and into main-stream medicine. The field has some natural advantages: Cardiovascular-associated genes tend to be tissue-specific—mainly expressed in the heart—which restricts the number of implicated genes. The abundance of structural and functional data about the detailed workings of cardiac proteins helps predict how genetic variants will alter function. Additionally, variants associated with cardiovascular disease are usually stable within an individual’s genome and his or her family members. De novo mutations (not found in either parent) can account for congenital heart disease and single-gene Mendelian disorders. Compared with the chaos of cancer genomes (especially solid tumors), which have many somatic mutations that vary throughout the tumor and evolve with time and treatment, cardiovascular genetic variation is tame and well-behaved.

There is, however, room to further maximize return. Short-read sequencing is ideal for identifying small genetic changes such as those that affect single or a few nucleotides. Cardiovascular diseases such as cardiomyopathies and arrhythmias tend to be caused by these small genetic changes. Larger structural genetic changes, ranging from hundreds to thousands of bases, are harder to define accurately when aligning short reads of DNA sequences. Newer sequencing technologies that use longer reads may be needed to reliably discover these larger genomic rearrangements.

So, what is the value of this genetic information? In the short term, the payoff is clear: a precise genetic diagnosis for the individual patient, which helps influence the choice of treatment with medications and devices. The same genetic information is also a diagnostic tool for family members to determine who is at risk for developing disease. The ability to assess and reduce risk is life-saving for those who have cardiovascular disorders, especially when dealing with diseases that have sudden death as a possible outcome. Moving forward, genetic information will permit clinicians and researchers to classify subtypes of heart failure, cardiomyopathy, and other cardiovascular diseases and to define better the cellular defects that cause hearts to fail and malfunction. The ultimate windfall will come from gene correction, through silencing or other genome editing.

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