Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or fiction?

Hypertrophic cardiomyopathy, affecting 1 in 500 persons, is the most common identifiable cause of sudden cardiac death in the young, whereas congenital long QT syndrome, affecting 1 in 5000 persons, is perhaps one of the most common causes of autopsy negative sudden unexplained death. Since May 2004, genetic testing has been available as a clinical diagnostic test for both hypertrophic cardiomyopathy and long QT syndrome. It is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice.

In 1990, the molecular underpinnings of hypertrophic cardiomyopathy were exposed with the identification of a mutation in the MYH7-encoded beta myosin heavy chain. Since then, hundreds of mutations scattered among at least 14 genes confer the pathogenetic substrate for this 'disease of the sarcomere'. In 1995, the discipline of cardiac channelopathies was born with the revelation that mutations in critical cardiac channel genes cause long QT syndrome. Today, hundreds of mutations involving several cardiac channel genes account for approximately 75% of long QT syndrome. Over the past decade, scores of genotype-phenotype correlation studies in both hypertrophic cardiomyopathy and long QT syndrome have been conducted.

Genomic medicine has now entered the clinical practice as it pertains to the evaluation and management of both hypertrophic cardiomyopathy and long QT syndrome. The diagnostic utility of genetic testing for both diseases is clearly evident, as well as current limitations. While treatment decisions are certainly influenced by knowing the underlying genotype in long QT syndrome, there seems to be negligible prognostic value associated with particular hypertrophic cardiomyopathy-causing mutations at this time.