Hypertrophic cardiomyopathy: from genetics to treatment.
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is the prototypic form of pathological cardiac hypertrophy. HCM is an important cause of sudden cardiac death in the young and a major cause of morbidity in the elderly.


METHODS
We discuss the clinical implications of recent advances in the molecular genetics of HCM.


RESULTS
The current diagnosis of HCM is neither adequately sensitive nor specific. Partial elucidation of the molecular genetic basis of HCM has raised interest in genetic-based diagnosis and management. Over a dozen causal genes have been identified. MYH7 and MYBPC3 mutations account for about 50% of cases. The remaining known causal genes are uncommon and some are rare. Advances in DNA sequencing techniques have made genetic screening practical. The difficulty, particularly in the sporadic cases and in small families, is to discern the causal from the non-causal variants. Overall, the causal mutations alone have limited implications in risk stratification and prognostication, as the clinical phenotype arises from complex and often non-linear interactions between various determinants.


CONCLUSIONS
The clinical phenotype of 'HCM' results from mutations in sarcomeric proteins and subsequent activation of multiple cellular constituents including signal transducers. We advocate that HCM, despite its current recognition and management as a single disease entity, involves multiple partially independent mechanisms, despite similarity in the ensuing phenotype. To treat HCM effectively, it is necessary to delineate the underlying fundamental mechanisms that govern the pathogenesis of the phenotype and apply these principles to the treatment of each subset of clinically recognized HCM.
Marian
Ali J
AJ
Center for Cardiovascular Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center and Texas Heart Institute at St. Luke's Episcopal Hospital, 6770 Bertner Street, Suite C900A, Houston, TX 77030, USA. ali.j.marian@uth.tmc.edu
D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000235:genetics*; D064211:Connectin; D016757:Death, Sudden, Cardiac / Q000209:etiology; D006801:Humans; D008967:Molecular Biology; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012307:Risk Factors
D064211:Connectin; D009124:Muscle Proteins; C577292:TCAP protein, human