(Circulation. 1995;91:1633-1640.)
© 1995 American Heart Association, Inc.
Articles |
Gene for Progressive Familial Heart Block Type I Maps to Chromosome 19q13
From the Department of Internal Medicine, University of Stellenbosch Medical School and Tygerberg Hospital (P.A.B.); the University of Stellenbosch and Medical Research Council Centre for Molecular and Cellular Biology, Department of Medical Physiology and Biochemistry, University of Stellenbosch Medical School (A.F., J.C.M., V.A.C.); the Section of Cardiology, Department of Medicine, Tygerberg Hospital (H.W.W); and the Section of Cardiology, Department of Pediatrics, Tygerberg Hospital, University of Stellenbosch Medical School (P.-L.van der M.), Tygerberg, South Africa.
Background Progressive familial heart block type I (PF-HBI) is a dominantly inherited cardiac bundle-branch conduction disorder that has been traced through nine generations of a large South African kindred. Similar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was to determine by linkage analysis the approximate chromosomal position of the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causative gene.
Methods and Results Eighty-six members of three pedigrees, 39
members of which were affected with PFHBI, were genotyped at four
linked 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 linkage versus nonlinkage) generated were 6.49 (
=0) for
the kallikrein locus, 5.72 (=0.01) for the myotonic dystrophy
locus,
3.44 (=0) for the creatine kinase muscle-type locus and 4.51
(=0.10) for the apolipoprotein C2 locus. The maximum multipoint
logarithm of the odds score was 11.6, with the 90% support interval
positioning the PFHBI locus within a 10 cM distance
centering on the kallikrein 1 locus.
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 these two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosis in the families studied and a foundation for cloning studies to identify the causative gene.
Key Words: conduction • bundle-branch block • mapping • genes
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