Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

Abstract

ObjectiveGenetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.MethodsWe performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.ResultsWe identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.ConclusionsOur data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.

Genetic Profile of the Dystrophin Gene Reveals New Mutations in Colombian Patients Affected with Muscular Dystrophinopathy

“…Large cohorts of patients analyzed in multiple European populations have shown a marked heterogeneity in the frequency of large deletions versus sequence variants, indicating the importance of ancestry in the dystrophin mutation profile. 43 Since 27.5% of all identified mutations were small deletions and point mutations, we support the use of both tools (sequencing and MLPA) for the molecular diagnosis of DMD/BMD. The MLPA has a sensitivity over 88%, 24 however, this tool has some limitations such as non-detection of changes that lie outside the target sequences analyzed by the probes or non-delimitation of deleted regions.…”

“…Large cohorts of patients analyzed in multiple European populations have shown a marked heterogeneity in the frequency of large deletions versus sequence variants, indicating the importance of ancestry in the dystrophin mutation profile. 43 …”

Mutation spectrum analysis of DMD gene in Indonesian Duchenne and Becker muscular dystrophy patients

“…However, in Kuwait and Malaysia, its applicability is reported to be much lower. 1,8,[27][28][29][30] Therapy using eteplirsen (skipping of exon 51) and golodirsen (skipping of exon 53), antisense oligonucleotide drugs approved by the FDA, can be applied in 23.25% of patients while codon read through therapy using compounds such as ataluren, can be applied in one patient.…”

Genetic Landscape of Dystrofin Gene Deletions and Duplications From Turkey: A Single Center Experience

“…DMD and BMD are the most common hereditary neuromuscular disease group of the childhood caused by the mutations which cause a defect in the synthesis of the fully-functional 427-kDa dystrophin protein (1)(2)(3)(4)(5)(6)(7)(8)(9). They make up approximately 50% of the neuromuscular diseases in our country (10).…”

“…Approximately twothirds of the considerably complex mutations in BMD/DMD are large deletions or duplications in one or more exons while the remainder is minor deletions, insertions, point mutations, and splicing mutations (1)(2)(3)(4)(5)(6)(7)(8)(9). Although the mutation frequency and spectrum depend on the country, DNA/RNA-based therapeutic approaches have rendered population-based genetic features more important in dystrophinopathies which still lack a curative treatment, especially in the last decade (5)(6)(7)(8)(9). Quantitative techniques such as microarray-based comparative genomic hybridization (array-CGH) and the more frequently utilized Multiple Ligation Probe Assay (MLPA) which detect the deletions and duplications are the first choices for the diagnosis of the disease (1)(2)(3).…”