Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy

Objectives The goal of this study was to perform comprehensive mutation analysis of the dystrophin gene in patients with X-linked dilated cardiomyopathy (XLCM). Background X-linked dilated cardiomyopathy is a familial disease that is characterized by congestive heart failure without clinical signs of skeletal myopathy. Mutations in the dystrophin gene have been associated with the X-linked form of dilated cardiomyopathy. However, the fraction of XLCM with dystrophin mutations and the distribution of those mutations is not clear. Technical difficulties previously limited comprehensive mutation analysis of this very large gene. Methods The Detection Of Virtually All Mutations-Single Strand Conformation Polymorphism (SSCP) (DOVAM-S), a robotically enhanced multiplexed scanning method that is a highly sensitive modification of SSCP, has successfully detected all of 240 mutations and polymorphisms in three blinded analyses of the factor VIII, factor IX, and ATM genes. Utilizing this method all 79 coding exons and splice junctions for the muscle dystrophin gene, along with six alternative exon 1 sequences, were scanned in eight patients with XLCM. Results This is the first comprehensive scanning of the dystrophin gene in XLCM. Three of eight patients have putative mutations, including two splicing mutations and a missense mutation at a highly conserved amino acid. Conclusions Mutations within the coding regions and splice junctions in the dystrophin gene only account for some cases of XLCM. Genetic heterogeneity and/or undetected mutations in auxiliary regulatory regions or deep within introns may occur in XLCM.