Genetic profile of Brazilian patients with dystrophinopathies

Abstract

Different types of mutations in the DMD gene underlie Duchenne muscular dystrophies (DMD) and Becker muscular dystrophies (BMD). Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included Multiplex Ligation-dependent Probe Amplification and Next generation sequencing (NGS) analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and 1 1.5 years old asymptomatic patient with persistent hiperCKemia. Overall, large deletions (58.2%) followed by nonsense mutations (12.4%) and large duplications (11.3%) were the most frequent variants in Brazilian families. Large deletions were less frequent in BMD than in DMD (44.8% vs 60.8%). We identified 19 new DMD variants. Nonsense mutations were significantly more frequent in patients from northeastern region than from southern/southeastern regions of Brazil (27.7% vs 8.5%, P < .05). Genetic profile of Brazilian patients with DMD/BMD is similar to previously reported cohorts, but it is not uniform across the country. This information is important to plan rational clinical care for patients in face of the new coming mutation-specific therapies.

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy

“…In‐frame deletion of exons 3–44 and exons 45–48 have been reported in four and two patients respectively who manifest DMD phenotype in the e‐Dystrophin database of in‐frame DMD mutations (http://edystrophin.genouest.org/). Deletion of exons 30–44 has also been previously been reported in a case of DMD (de Almeida et al, ) while duplication of exons 45–49 have been reported in three DMD patients (http://edystrophin.genouest.org/) and one patient with mild DMD phenotype (Pikó et al, ). Further studies at the mRNA transcript levels can clarify the underlying genetic mechanisms for the discrepancies for these cases.…”

Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction DMD Gene Result: A Study Including Targeted Next-Generation Sequencing

“…Easier access to sequencing technology along with growing interest in genotype-based treatments [3] and the development of potential gene-editing therapies [5], has motivated the recent characterization of numerous small pathogenic variants in dystrophinopathy patients bearing a previous normal result on MLPA. Studies have been done in patients of Latin American descent [40,41] and in other countries reporting their first sequencing experiences in the neuromuscular diagnostic setting [38,42]. The diagnosis success rates of these studies have varied widely, from 27% [42] to nearly 100% [40].…”

“…Studies have been done in patients of Latin American descent [40,41] and in other countries reporting their first sequencing experiences in the neuromuscular diagnostic setting [38,42]. The diagnosis success rates of these studies have varied widely, from 27% [42] to nearly 100% [40].…”

“…Missense single-nucleotide substitutions are considered to be infrequent dystrophinopathy-causing genotypes that account for less than 2% of these cases [39,40,43]. Most of them abolish the ability of dystrophin to bind to the actin cytoskeleton or to the extracellular matrix through a beta-dystroglycan linkage [3].…”

Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystrophy

“…35 This distribution is supported by a number of studies. 23,36,37,46,[106][107][108][109][110] It is therefore practical to test for DMD gene mutations in order of frequency. The consensus group agreed on 3 statements that outline the recommended steps needed to reach a complete genetic diagnosis of DMD (Figure 3).…”