Novel compound heterozygous mutations of the myosin heavy chain gene in patients with hypertrophic cardiomyopathy

bACkgRouNd: Hypertrophic cardiomyopathy (HCM) is a multifactorial disorder, with mutations implicated in 14 sarcomeric and cytoskeletal genes, leading to genotypic and phenotypic heterogeneity, and a challenging genetic and clinical diagnosis. The genetic characteristics of HCM have been studied for more than two decades in various ethnic and racial groups, and many novel genetic variations have been reported. The myosin heavy chain gene is the most heavily implicated gene in HCM, with >200 reported mutations, the majority of which have been found in the head-rod junction. The rod portion of MYH7, coded by exons 29 to 40 and belonging to the light meromyosin (LMM) region, has not been characterized to the same extent as the head domain with respect to single-nucleotide polymorphisms (SNPs)/mutations. obJECTIVE: To screen the conserved LMM region, constituting exons 27 to 39 (13 exons), to identify any pathogenic SNPs/variations in this region in a population of Indian patients. METhodS: Molecular screening was performed by polymerase chain reaction-based single-strand conformation polymorphism analysis in 100 control individuals and 100 HCM patients. The variations were confirmed by sequencing. Insilico analysis was performed to analyze the effect of the respective variations. RESuLTS: Screening of exons 27 to 39 revealed three novel missense variations and one novel synonymous variation in exon 34. Interestingly, patients with these variations also exhibited compound heterozygosity, indicating exon 34 to be the ‘hotspot’ exon of the LMM region. CoNCLuSIoN: The results of the present study emphasize the importance of the LMM (rod) region of the MYH7 gene and suggest that variations in the conserved region are likely to be more pathogenic, making screening of the entire gene for HCM diagnosis mandatory.