A gene locus for progressive familial heart block type II (PFHBII) maps to chromosome 1q32.2-q32.3.
Cardiac conduction defects that are associated with dilated cardiomyopathy (DCM) are generally considered to be sporadic clinical entities, although familial forms of disorders with these clinical features have been identified in a number of families in different countries. An autosomal dominant cardiac disorder characterised by conduction abnormalities and DCM, termed progressive familial heart block type II (PFHBII) (OMIM 140400), has been described in a South African Caucasian family of Northern European descent. Known candidate loci for isolated conduction disorders, isolated DCM and conduction disorders complicated by DCM were excluded from disease causation in this family by linkage analysis, with the exception of the DCM-associated (CMD1D) locus on chromosome 1q32, where a maximum multipoint lod score of 3.7 in the interval between D1S3753 and D1S414, was generated. This region encompassed the troponin T gene (TNNT2), however, genetic fine mapping and haplotype analysis excluded TNNT2 as cause of PFHBII and placed the disease-causative gene within a 3.9 cM (2.85 Mb) interval, flanked by D1S70 and D1S505. Analysis of KCNH1, KIAA0205, LAMB3 and PPP2R5A, which map within the critical interval, indicated that the PFHBII-causative mutation does not lie within the coding regions or splice junctions of these plausible candidate genes. The data indicate the existence of a novel locus involved in the pathogenesis of cardiac conduction abnormalities and DCM.