Genetics of hypertrophic cardiomyopathy: one, two, or more diseases?

Hypertrophic cardiomyopathy is the most common identifiable cause of sudden death in the young. This review details the history of hypertrophic cardiomyopathy, recent discoveries in its genetic underpinnings and important genotype-phenotype relationships described in recent studies.

Since the discovery of the genetic underpinnings of hypertrophic cardiomyopathy in 1989 hundreds of mutations scattered among at least 10 sarcomeric genes confer the pathogenetic substrate for this 'disease of the sarcomere/myofilament'. More recently, the genetic spectrum of hypertrophic cardiomyopathy has expanded to encompass mutations in Z-disc-associated genes (Z-disc hypertrophic cardiomyopathy) and glycogen storage diseases mimicking hypertrophic cardiomyopathy (metabolic hypertrophic cardiomyopathy). Recent genotype-phenotype studies have discovered an important relationship between the morphology of the left ventricle, its underlying genetic substrate and the long-term outcome of this disease.

Genomic medicine has entered clinical practice and the diagnostic utility of genetic testing for hypertrophic cardiomyopathy is clearly evident, but with the growing number of hypertrophic cardiomyopathy-associated genes strategic choices have to be made. With recent discoveries in genotype-phenotype relationships, especially pertaining to the echocardiographic septal shape and the underlying pathogenetic mutation, time has come to subdivide the one disease we call hypertrophic cardiomyopathy.