Mutation Type Is Not Clinically Useful in Predicting Prognosis in Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM), or clinically unexplained hypertrophy of the heart, is a common genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. As the genetic mutations underlying the pathogenesis of this disease have been identified, investigators have attempted to link mutations to clearly defined alterations in survival in hopes of identifying prognostically relevant biomarkers of disease. While initial studies labeling particular MYH7 -encoded beta myosin heavy chain and TNNT2 -encoded cardiac troponin T mutations as “malignant” or “benign” raised hopes for mutation-specific risk stratification in HCM, a series of subsequent investigations identified mutations in families with contradictory disease phenotypes. Furthermore, subsequent proband-based cohort studies indicated that the clinical prognostic relevance of individual mutations labeled as “malignant” or “benign” in large referral centers is negligible. Herein, we seek to summarize the controversy and dispute the notion that mutation-specific risk stratification in HCM is possible at the present time. We provide evidence for clinicians and basic scientists alike to move beyond simple mutation descriptors to a more nuanced understanding of HCM mutations which fully captures the multi-factorial nature of HCM disease expression. Response by Ho on p 2450 Over the last 2 decades, the genetic underpinnings of heritable cardiovascular disease have begun to be unveiled, starting with the discovery of rare pathogenic mutations that cause cardiomyopathies and cardiac channelopathies. The simple paradigm of Mendelian inheritance, while helpful in certain monogenic disease processes, is fundamentally incapable of explaining the entirety of how complex diseases express in the context of complex human physiology under the influence of a myriad of intrinsic and extrinsic variables. Our understanding of the intricate interplay between 1 such intrinsic variable, the genome, and the manifestation of disease was advanced significantly in the decoding of a handful of human's genomes in February of 2001.1,2 Despite the decade …