Genetic profile of Brazilian patients with dystrophinopathies

Duchenne (DMD) and Becker (BMD) muscular dystrophies are the most frequent myopathies in children and caused by mutations in the DMD gene. Little is known about the genetic profile of DMD/BMD in Brazilian patients. This information is important because mutation-specific genetic therapies are shortly coming. To characterize the genetic profile of Brazilian patients with DMD/BMD, we selected all patients with molecular diagnosis of dystrophinopathies followed at UNICAMP neuromuscular outpatient clinic between March 2015 and 2016. Each patient underwent molecular investigation that included MLPA and gene sequencing (small mutations). For those variants not previously reported, we looked at the available SNP and mutation databases (1000 genomes consortium, ExAC, NCBI and Ensembl) and also performed in silico analyses using different tools (Mutation taster, Polyphen2, Sift). We collected data on age at disease onset and duration and disease severity (using the MFM scale) in order to compare patients with large vs small mutations. We recruited 41 patients. Mean age at disease onset was 3.3 years (range 1–10); 19 patients were wheelchair users and 22 ambulant. Large deletions and duplications were found in 30 (73.2%) and point mutations in 9 (26.8%). In the later group, nonsense mutations were found in 3 patients from 2 unrelated families (7,3%) and frameshift mutations in 6 patients from 5 unrelated families (14.6%). We identify a novel intronic mutation (c.2803 + 5G > C) that was found in two brothers, one DMD other BMD phenotype. Genotype–phenotype analyses revealed no significant difference between patients with small vs large mutations in terms of disease progression and age at onset. Large deletions and duplications at the DMD gene are the most frequent genetic substrate in Brazilian patients. Small mutations were found in 26.8% of the patients. This profile is similar to that reported in European and North American cohorts.