E ditor—Familial hypertrophic cardiomyopathy (FHC) is a prevalent dominantly inherited disease characterised by unexplained hypertrophy of the heart muscle. The clinical manifestations are heterogeneous and the disease is a leading cause of sudden cardiac death among young, otherwise healthy people. 1 More than 120 different mutations have been reported in the following eight genes encoding sarcomeric polypeptides given in parentheses: TNNT2 (troponin T), MYL3 (essential myosin light chain), MYH7 (β myosin heavy chain), MYBPC3 (myosin binding protein C), MYL2 (regulatory myosin light chain), TPM1 (α tropomyosin), ACTC (α cardiac actin), andTNNI3 (troponin I). 2 3 Furthermore, a disease locus on chromosome 7 has been linked to FHC, but the gene has not yet been identified. 4 Additional disease genes probably remain to be discovered since two recent studies found that it was only possible to genotype 50-60% of the FHC population by mutation analyses of seven disease genes. 5 6 In order to optimise risk stratification and management of FHC patients, it is important to identify all disease carriers, which is difficult by physical examination because of the age dependent penetrance of the disease. However, disease carriers may be identified by use of genetic diagnosis, although it is laborious because of the large number of disease genes and the pronounced allelic heterogeneity of the disease loci, with the majority of affected families having their own “private” missense mutation. 7 In addition, genetic diagnosis is complicated by the fact that several amino acid polymorphisms occur in most of the FHC genes 8 9 (unpublished observations). Given this complex genetic background, the use of linkage analysis can be beneficial as it may identify the most likely disease gene and provide evidence for exclusion of some or all of the other candidate disease loci even in small families. 10

It was the aim of the present study to develop a firm basis for efficient use of linkage analysis in genetic diagnosis of FHC by a well founded selection of polymorphic markers defining nine FHC loci, including a refined genetic mapping of the troponin T gene in a 4 cM interval. For rapid analysis, multiplex PCR panels were developed comprising all markers selected. The feasibility of the method was evaluated by identification of mutations in three families of varying size.