The recent evolution of molecular genetic techniques and their application in deciphering the molecular genetic basis of inherited diseases have facilitated the dawning of molecular medicine. A complete genetic map of the human genome, based on easily identifiable highly polymorphic DNA markers, has been developed. 1 2 3 This achievement is a milestone in that it provides the foundation for genetic linkage analysis, a technique essential to the mapping of the chromosomal locus responsible for a disease. Before the development of multiple informative markers, identification of a disease-related gene required a priori knowledge of the defective protein, which was known for only a few diseases. The previous approach of “from a defective protein to a defective gene” has been replaced with the approach of “from a defective gene to a defective protein.” The recent availability of the highly informative STRP markers compared with previous markers based on RFLP has greatly accelerated chromosomal mapping by linkage analysis. 4 Furthermore, the RFLP markers detected by Southern blotting required 5 to 7 days, whereas STRP markers are detected by PCR and require as few as 1 to 2 days. 4 5 The loci for more than 400 disease-related genes have been mapped, and the responsible genes have been identified for more than 40 of these diseases. 1 Theoretically, it is possible to map the chromosomal locus of any disease-related gene if a family with 10 or more living affected individuals spanning two or more generations is available. 4 5 Subsequent to the chromosomal mapping of the locus by genetic linkage analysis, several techniques, such as positional cloning, are used to identify the responsible gene. 6 7 Positional cloning refers to cloning of a segment of DNA with only its chromosomal position in relation to a marker known. This process of identifying the genes, which may require years, has been accelerated recently through the development of two techniques: YAC and PFGE. 8 Before the availability of YAC, one could clone fragments of DNA only as large as 45 000 bp, whereas with YAC, it is possible to clone fragments as large as 1 to 2 million bp. Separation of DNA fragments by agarose gel electrophoresis was limited to those of≤ 10 000 bp, whereas with PFGE, fragments as large as 2 million bp can be separated.

HCM was the first primary cardiomyopathy that was subjected to these techniques. During the short period of 4 years, three genes and a fourth locus responsible for this disease have been identified. 9 10 11 12 In addition, structure-function analysis has shed significant light on the molecular basis of this disease. It is hoped that within the next few years the application of molecular genetic tools will not only facilitate the ability to diagnose HCM but also help to stratify and develop more definitive therapy.