Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD). Germline mutations in genes encoding for sarcomere proteins are found in more than half of the cases of unexplained LVH. The autosomal dominant inherited forms of HCM are characterised by incomplete penetrance and variability in clinical and echocardiographic features, prognosis and therapeutic modalities. The identification of the genetic defect in one of the HCM genes allows accurate presymptomatic detection of mutation carriers in a family. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD, which can be the first manifestation of the disease in asymptomatic persons. In this article we present our experience with genetic testing and cardiac screening in our HCM population and give an overview of the current literature available on this subject. (Neth Heart J 2007;15:184-9.) Keywords: hypertrophic cardiomyopathy, genetics T he prevalence of unexplained left ventricular hypertrophy (LVH) in the general population is estimated to be 1 in 500.1,2 Hypertrophic cardiomyopathy (HCM) caused by genetic defects in sarcomere genes may account for up to 60% of cases of LVH. This makes HCM the most common genetic cardiovascular disorder.3,4 The first HCM gene was identified in 1990;5 since then more than 11 HCM genes, mostly encoding for one of the sarcomere proteins, have been identified.HCM is the most common cause of sudden death (SD) in the young and a major cause of morbidity and mortality in the elderly.6 SD may be the first manifestation of the disease in an asymptomatic individual. Many studies in HCM have shown extensive variability in expression, prognosis and therapy, even within families. Identification of disease-causing genetic defects in familial HCM allows reliable identification of at-risk relatives. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD.Genetic studies in HCM At present, more than 400 disease-causing mutations in 11 genes, mostly encoding one of the myocardial contractile proteins (table 1), have been identified in familial HCM. In approximately 60% of HCM families a sarcomere mutation is identified. 3,7,8 Diseasecausing mutations are identified in 60% (142/ 236) of the HCM families currently being followed and completely genotyped for eight HCM genes in Rotterdam.At the cardiogenetics clinic of the Erasmus Medical Centre in Rotterdam, the molecular analysis of HCM involves initial screening for the three Dutch founder mutations in the MYBPC3 gene. In the absence of the founder mutations, subsequently the MYBPC3 and the MYH7, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), regulatory and essential myosin light chain, α-actin, α-tropomyosin are sequenced. DNA sequencing is time ...