Author + information
- Linnea M. Baudhuin, PhD∗ (, )
- Katrina E. Kotzer, MS, CGC,
- Michelle L. Kluge, MS, CGC and
- Joseph J. Maleszewski, MD
- ↵∗Mayo Clinic, Laboratory Medicine and Pathology, 200 First Street SW, Rochester, Minnesota 55905
In a recent paper by Semsarian et al. (1), several arguments are presented indicating that the prevalence of clinically expressed and hypertrophic cardiomyopathy (HCM) gene carriers has been greatly underestimated and could be as high as 1:200. This updated frequency estimate was primarily on the basis of a genetic analysis, published in 2012, that demonstrated 22 of 3,600 participants from the Framingham Heart Study and Jackson Heart Study cohorts had likely pathogenic or pathogenic sarcomeric gene variants (2). Although Semsarian et al. (1) stated that the variants were classified “using stringent criteria for pathogenicity,” it is important to note that since 2012, there have been significant advancements in the tools to aid in variant classification (i.e., determining whether a variant is benign or pathogenic).
Technological advances have allowed us to more comprehensively and efficiently interrogate human genomes, and there are a number of large-scale efforts, such as the Exome Sequencing Project and Exome Aggregation Consortium, which have been publishing genomic data and variant frequencies from very large populations stratified by ethnicity. These large-scale efforts are important for variant classification because they provide population minor allele frequencies that, when used in concert with disease prevalence estimates, may push a variant into a benign or pathogenic category. Furthermore, databases such as ClinVar (3) and Human Genome Mutation Database make it easier for us to access variant classifications and publications by different clinical laboratories and groups. Variant data, from even just a few short years ago, should be reviewed through the lens of these new resources, and revisited accordingly, in this rapidly changing landscape.
As such, we took a closer look at the 22 variants classified as pathogenic or likely pathogenic by Bick et al. (2). The vast majority (20 of 22) of these variants were missense variants, which tend to be less straightforward to classify. Interestingly, only 4 of the 22 individuals actually expressed HCM (but were not specified by Bick et al. ). Utilizing our criteria for variant classification, which is largely on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines for variant interpretation (4) and utilizes databases and resources listed in the preceding text, only 6 of these variants could be confidently classified as likely pathogenic or pathogenic (i.e., 6 of 3,600, or approximately 1:600 HCM gene carrier frequency). In viewing ClinVar data, we observed that the Harvard Laboratory for Molecular Medicine (whom participated in the original Bick et al.  variant classification) currently classifies 12 of the 22 variants as variants of uncertain significance (equating to an HCM gene carrier frequency of 1:360).
Assessment of these 22 variants illustrates the somewhat subjective and rapidly evolving nature of genetic variant classification. After applying contemporary variant classification strategies to the 2012 data, the resultant data would not support a frequency as high as 1:200. Rather, it would seem to continue to support the 1:500 frequency of the disease more prevalently referenced in the published data. This frequency would take into account reduced penetrance (i.e., gene-positive, phenotype-negative cases), as well as HCM cases with nongenetic causes. With that said, these numbers will likely continue to change as our variant interpretation strategies continue to evolve. More standardized variant classification criteria would be helpful and improvements in that area have been made (3,4). However, the complexities of variant classification will likely continue to leave this field somewhat in flux, and the example with HCM presented here is likely just the tip of the iceberg.
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