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

Neri, Marcella; Rossi, Rachele; Trabanelli, Cecilia; Mauro, A. Di; Selvatici, Rita; Falzarano, Maria Sofia; Spedicato, N.; Margutti, Alice; Rimessi, Paola; Fortunato, F.; Fabris, M.; Gualandi, Francesca; Comi, Giacomo Pietro; Tedeschi, Silvana; Seia, Manuela; Fiorillo, Chiara; Traverso, Monica; Bruno, Claudio; Giardina, Emiliano; Piemontese, Maria Rosaria; Merla, Giuseppe; Cau, Milena; Marica, Monica; Scuderi, Carmela; Borgione, Eugenia; Tessa, Alessandra; Astrea, Guja; Santorelli, Filippo M.; Merlini, Luciano; Mora, Marina; Bernasconi, Pia; Gibertini, Sara; Sansone, Valeria; Mongini, Tiziana; Berardinelli, Angela; Pini, Antonella; Liguori, Rocco; Filosto, Massimiliano; Messina, Sonia; Vita, Gianluca; Toscano, Antonio; Pane, Marika; Servidei, Serenella; Pegoraro, Elena; Bello, Luca; Travaglini, Lorena; Bertini, Enrico; D’Amico, Adele; Ergoli, Manuela; Politano, Luisa; Torella, Annalaura; Nigro, Vincenzo; Mercuri, Eugenio; Ferlini, Alessandra

doi:10.3389/fgene.2020.00131

Cited by 62 publications

(68 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“… 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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…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.…”

Section: Genetic Pathogenesis Of Dmdmentioning

confidence: 99%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

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Shen

Zhang

et al. 2020

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Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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“…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.…”

Section: Plos Onementioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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A nonsense mutation adds a premature stop signal that hinders any further translation of a protein-coding gene, usually resulting in a null allele. To investigate the possible exceptions, we used the DMD gene as an ideal model. First, because dystrophin absence causes Duchenne muscular dystrophy (DMD), while its reduction causes Becker muscular dystrophy (BMD). Second, the DMD gene is X-linked and there is no second allele that can interfere in males. Third, databases are accumulating reports on many mutations and phenotypic data. Finally, because DMD mutations may have important therapeutic implications. For our study, we analyzed large databases (LOVD, HGMD and ClinVar) and literature and revised critically all data, together with data from our internal patients. We totally collected 2593 patients. Positioning these mutations along the dystrophin transcript, we observed a nonrandom distribution of BMD-associated mutations within selected exons and concluded that the position can be predictive of the phenotype. Nonsense mutations always cause DMD when occurring at any point in fifty-one exons. In the remaining exons, we found milder BMD cases due to early 5' nonsense mutations, if reinitiation can occur, or due to late 3' nonsense when the shortened product retains functionality. In the central part of the gene, all mutations in some in-frame exons, such as in exons 25, 31, 37 and 38 cause BMD, while mutations in exons 30, 32, 34 and 36 cause DMD. This may have important implication in predicting the natural history and the efficacy of therapeutic use of drug-stimulated translational readthrough of premature termination codons, also considering the action of internal natural rescuers. More in general, our survey confirm that a nonsense mutation should be not necessarily classified as a null allele and this should be considered in genetic counselling.

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

Cited by 62 publications

References 55 publications

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

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

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

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

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