The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Abstract

in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein d o m a i n , w i t h e ff e c t s on p o p u l a t i o n ge n e t i c c h a r a c t e r i s t i c s a n d ne w personalized therapies.

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

“…We may firstly consider that some DMD mutations may have escaped MLPA and sequencing testing, as for atypical mutations occurring in regulatory regions or due to deep intronic variants/rearrangements. 20 Because these are estimated to be less than 1% in various patient series, 21 , 22 , 23 , 24 their impact on the detection rate should be low, and only a few cases might have been missed. Ethnicity may also play a role in mutation type frequency, as already described 23 ; only the adoption of a single and fully accurate method able to detect all mutation types, such as whole-genome sequencing (WGS), will allow us to unravel these events and their frequency in the various populations.…”

“… 20 Because these are estimated to be less than 1% in various patient series, 21 , 22 , 23 , 24 their impact on the detection rate should be low, and only a few cases might have been missed. Ethnicity may also play a role in mutation type frequency, as already described 23 ; only the adoption of a single and fully accurate method able to detect all mutation types, such as whole-genome sequencing (WGS), will allow us to unravel these events and their frequency in the various populations. 25 Second, a few patients referred as DMD/BMD or generally as possible dystrophinopathies may represent phenocopies of other clinical entities like limb-girdle muscular dystrophies (LGMDs) or other rare hereditary myopathies.…”

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

“…Genetic analysis of DMD patients showed that large deletions are the most common type of mutations worldwide (64% in Oceania, 66% in Europe, 70% in Americas, 72% in Asia, and 88% in Africa). Population-based cohort studies (Chinese [ 16 ], Spanish [ 17 ], and Italian [ 18 ]) also manifested racial characteristics of DMD mutation types.…”

The position of nonsense mutations can predict the phenotype severity: A survey on the DMD gene

“…On the other hand, if a portion of mRNA skips the exon with a mutation, a smaller protein could still be produced on the condition that the skipped exon is in-frame. Previous works hypothesized that mutations in in-frame exons might cause milder phenotypes via spontaneous exon skipping of the mutated exon, which may weaken the mutation consequence [14,37]. This favorable precondition is the rule for most central dystrophin exons: all of them between 23 and 42 are in-frame.…”

“…The first nonsense variants and other small defects were only identified six years after the DMD gene cloning [12,13]. Unlike most disease genes, single nucleotide substitutions and small insertion/deletion of bases are a less frequent cause of disease [14,15]. Random nonsense mutations were found in 10-15% of DMD cases [16].…”