Pathogenicity of Hypertrophic Cardiomyopathy Variants: A Path Forward Together.

Abstract

The challenges of correctly interpreting rare variants identified via genetic testing of patients with hypertrophic cardiomyopathy (HCM) are universal and ever present. HCM genetic testing has been offered for almost 2 decades, yet in spite of the leaps forward in our understanding, the genetic underpinnings of this disease remain elusive in many patients. Mainstream application of comprehensive cardiac gene panels, which are becoming more affordable as the technology develops, detect a clinically significant variant in 40% to 60% of patients with the majority of variants residing in genes encoding the cardiac sarcomere.1,2 The value of identifying a pathogenic variant in a proband extends to family members, who have the option to know conclusively whether they carry the causative variant, allowing more targeted clinical surveillance and clarifying risk to children. For many others, however, the identification of uncertain variants poses greater challenges, and the expertise, resources, and standardized criteria to classify them as causative or benign currently fall short. See Article by Furqan et al In this issue of Circulation: Cardiovascular Genetics , Furqan et al3 demonstrate the marked discordance seen between specialist HCM centers worldwide. Among sarcomeric human cardiomyopathy registry centers, 20.5% of variants seen in >1 center had classification discrepancies that impacted clinical management, that is, likely pathogenic/pathogenic or variant of uncertain significance or likely benign/benign. The primary reason, in 75% of cases, was access to privately held data by either the sarcomeric human cardiomyopathy registry center (60%) or from the genetic testing laboratory’s internal experience (60%). Segregation information from informative families accounted for 35% of discordant variants, …