Author + information
- Christopher Semsarian, MBBS, PhD, MPH,
- Jodie Ingles, GradDipGenCOuns, PhD, MPH,
- Martin S. Maron, MD and
- Barry J. Maron, MD∗ ()
- ↵∗Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 620, Minneapolis, Minnesota 55407
We thank Dr. Baudhuin and colleagues for their letter regarding our recent article (1). They raise the very important and topical issue of DNA variant classification in determining whether a genetic finding is pathogenic, benign, or a variant of uncertain significance (VUS). As Dr. Baudhuin and colleagues would be aware, major international initiatives are being established to develop robust and reliable classification criteria to determine the pathogenicity of DNA variants in hypertrophic cardiomyopathy (HCM), and indeed all other cardiovascular genetic diseases. Such classification systems and variant interpretation need to take into account rapidly evolving human genetic databases such as the Exome Aggregation Consortium (ExAC), 1000 Genomes Project, Exome Variant Server (ESV), and most recently, the Genomics England 100,000 Genomes Project, as well as in silico tools (such as polyphen2 and SIFT), functional data, and cosegregation studies in families.
Significantly, the final outcome of the genetic evaluation is “probabilistic,” that is, it is not a “yes/no” answer but rather a probability that the variant identified causes disease on the basis of the available supporting evidence (2,3). Dr. Baudhuin and colleagues correctly point out that over time, variant classifications can change due to new information, and this can change the classification from pathogenic to VUS or benign, and alternatively from VUS to pathogenic. We agree that this is a product of the rapid escalation of available genetic information due to newer, faster, and cheaper sequencing technologies, and highlights the importance of periodic re-evaluation of all variants. In HCM, we have previously reported that reclassification is required in up to 10% of families with HCM (4). Furthermore, the issues surrounding variant classification highlight the urgent need to have organized collaborative international efforts to curate all human disease genes and to develop classification systems directly relevant to cardiovascular disease. The recently published American College of Medical Genetics and Genomics guidelines are an important first step in this process, but need significant adaptation and modification for such guidelines to be reliable and accurate in the specific interpretation of variants relevant to cardiovascular disease. To this end, the recently developed National Institutes of Health–funded Clinical Genome Resource (ClinGen) initiative provides the hope of improving genomic interpretation by a coordinated international effort from both clinical and research communities, with the key goals to share data, build knowledge, develop and refine variant classification, and improve care.
Importantly, the revised estimated prevalence of HCM of up to 1 in 200 people is on the basis of several factors in addition to the rate of pathogenic mutations in what are known as highly intolerant sarcomere genes. Advanced imaging techniques with high-resolution cardiovascular magnetic resonance provide more reliable diagnosis by identifying left ventricular hypertrophy not appreciated with echocardiography, expanded recognition of the genotype-positive, phenotype-negative subset, while more comprehensive family-based clinical and genetic surveillance and higher clinical index of suspicion is resulting in more asymptomatic patients being identified with HCM (Central Illustration in Semsarian et al. ). Taking together all of these considerations, HCM appears more prevalent than current estimates, promoting greater visibility for the disease, enhancing diagnosis and consideration of contemporary treatment options (5), and ultimately improving care and outcomes in patients and families with HCM worldwide.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Semsarian C.,
- Ingles J.,
- Maron M.S.,
- Maron B.J.
- Maron B.J.,
- Maron M.S.,
- Semsarian C.
- Maron B.J.,
- Ommen S.R.,
- Semsarian C.,
- Spirito P.,
- Olivotto I.,
- Maron M.S.