Genetic heterogeneity for autosomal dominant familial hypertrophic cardiomyopathy in a Pakistani family

ABSTRACT

To identify the gene causing inherited hypertrophic cardiomyopathy [HCM] in a Pakistani family. Cross-sectional, observational study. Department of Cardiology, Shifa International Hospital and Biomedical and Genetic Engineering Laboratories, Islamabad, from 2005 to 2007. A large family of 17 individuals was included in this study. In the family 6 members were suffering from hypertrophic cardiomyopathy. Linkage analysis was carried out to map the disease-causing gene. Genomic DNA from each individual of the whole family was genotyped for microsatellite markers for all the known HCM loci followed by a whole genome search. Automated DNA sequencing was done for mutation identification in the candidate genes. Linkage analysis of 17 family members showed a maximum two point Lod score of 3.97 with marker D1S1660 at chromosome 1q 32.2. A disease region of 4.16cM was defined by proximal and distal cross-overs with markers GATA135F02 and D1S3715 respectively. This region contained the candidate genes TNNT2 [cardiac troponin T] and TNNI1 [troponin I 1]. Direct sequencing of these genes for the whole family containing 17 members showed no diseaseassociated mutation in either of these genes. Through linkage analysis, a disease locus for HCM family was mapped within a region of 4.16cM at chromosome 1q31.3-q32.1. So far no disease-associated mutation has been found in the candidate genes