GENE FOR PROGRESSIVE FAMILIAL HEART-BLOCK TYPE-I MAPS TO CHROMOSOME 19Q13

Background Progressive familial heart block type I (PF-HBI) is a domin antly inherited cardiac bundle-branch conduction disorder that has bee n traced through nine generations of a large South African kindred. Si milar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was t o determine by linkage analysis the approximate chromosomal position o f the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causa tive gene. Methods and Results Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four l inked polymorphic marker loci mapped to chromosome 19, bands q13.2-q13 .3 (chromosome 19q13.2-13.3). Maximum two-point logarithm of the odds scores (which represent the logarithm of the odds ratio of detecting l inkage versus nonlinkage) generated were 6.49 (Theta=0) for the kallik rein locus, 5.72 (Theta=0.01) for the myotonic dystrophy locus, 3.44 ( Theta=0) for the creatine kinase muscle-type locus and 4.51 (Theta=0.1 0) for the apolipoprotein C2 locus. The maximum multipoint logarithm o f the odds score was 11.6, with the 90% support interval positioning t he PFHBI locus within a 10 cM distance centering on the kallikrein 1 l ocus. Conclusions The gene for PFHBI maps to an area of approximately 10 cM on chromosome 19q13.2-13.3. There are several candidate genes in this interval; although a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHBI, the proximity of t hese two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosi s in the families studied and a foundation for cloning studies to iden tify the causative gene.