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

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

Localization of DFNB28 locus in a Pakistani consanguineous kindred

To determine the disease locus involved in autosomal recessive nonsyndromic deafness. Five generations of a Pakistani sheikh consanguineous family suffering from nonsyndromic deafness was ascertained from the Punjab province. The molecular studies were carried out at Biomedical and Genetic Engineering Division, KRL, Islamabad. Fifteen family members [five affected and ten normal] were processed for molecular studies. All marriages were consanguineous. Linkage analysis for known loci of autosomal recessive non-syndromic deafness was carried out. Two point lod score analysis resulted in maximum lod score [Z max] 4.35 for marker D22S445 at 6 = 0. Significant linkage was found with DPNB28 locus at chromosome 22 [22ql3]

Identification of LCA 4 locus in a Pakistani consanguineous kindred suffering from Leber's congenital amaurosis

To determine the disease locus involved in autosomal recessive Leber's Congenital Amaurosis. Biomedical and Genetic Engineering Division, KRL, Islamabad. Five generations of a Pakistani consanguineous family suffering from congenital blindness [Leber's Congenital Amaurosis] was studied. Genomic DNA was amplified across the polymorphic micro satellite markers. Polymerase chain reaction [PCR] products were separated by non-denaturing polyacrylamide gel electrophoresis. Alleles were assigned to individuals. LOD score calculations were done using the Cryllic and MLINK software program. Molecular studies were done in 29 individuals of the family of whom 11 were blind and 18 were normal. Of eleven blind individuals six were males and five females. Linkage analysis for known loci of autosomal recessive LCA loci was carried out. Two point LOD score analysis with LCA 4 locus [17p13.1] resulted in maximum lod score [Z max] of 4.75 for marker D17S796 at q=0. Significant linkage was found with LCA4 locus [17p13.1]