Mutation Spectrum of Dystrophinopathies in India: Implications for Therapy

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Dystrophinopathies are common X-linked recessive neuromuscular disorders caused by pathogenic variants in the dystrophin gene (DMD). Analysis of the mutational spectrum in the Indian patients would be useful for confirming the diagnosis, provide genetic counseling, offer reproductive options, and importantly to determine the eligibility for the mutation-specific therapies currently approved/or undergoing trials, such as skipping of specific exons or read-through of stop codon. In 1660 patients diagnosed as Duchenne muscular dystrophy (DMD) /Becker muscular dystrophy (BMD) deletion- duplication analysis of all 79 exons was carried out using Multiplex ligation-dependent probe amplification(MLPA) technology. In 63 patients where no mutations were detected by MLPA, the nucleotide sequence of the DMD gene was determined by next gene sequencing. In seven cases where MLPA showed deletion of a single exon, and amplification of the specific exon was successful by polymerase chain reaction (PCR), Sanger sequencing of the concerned region was carried out to detect changes in the sequence. The mutation spectrum of 1660 patients with DMD/BMD was determined and 1188 (71.6%) patients were identified to have deletions or duplications of one or more exons. Of these, 1090 (65.7%) had true deletions of exons and 98 (5.9%) had duplications of exons. The most frequent change was the deletion of exon 45 (66/1090, 6.1%) and duplication of exon 2 (1/98, 11.2%). Sequencing of dystrophin gene was performed in 70 cases, and variants were identified in 68 patients (97.1% of those analyzed). Stop codon variants were observed in 34 (50%) patients, missense variants in 4 (5.9%), small deletions in 19 (27.9%), small insertions in 6 (8.8%) and slice site variants in 5 (7.4%) patients. Thirty one of 68 variants (45.5%) were novel. The authors highlight the importance of identifying the type of mutation in patients with DMD. Based on the results, it is estimated that 681 (54.2%) of 1256 patients in this cohort would benefit from the currently ongoing mutation-specific therapies.