Reassessing carrier status for dystrophinopathies

Abstract

The cloning of the DMD gene, and the identifications of mutations in it as the cause of Duchenne muscular dystrophy (DMD), makes a compelling story that is aptly told elsewhere.¹ The locus-the largest in the human genome-consists of 79 exons, distributed over 2.5 million nucleotides on the X chromosome, which are assembled into a complementary DNA (cDNA) of around 14 kb encoding the predominant muscle isoform of the dystrophin protein.² The size of the gene, and the number of exons, had historically made mutation analysis challenging. For more than a decade, the standard clinical assay was a multiplex PCR test that amplified sequences from a limited number of exons; nevertheless, because it included exons within the deletion hotspots of the gene, this method could confirm the presence of mutations in up to 98% of boys with exonic deletions.^3,4.