Neri Marcella, Rossi Rachele, Trabanelli Cecilia, Mauro Antonio, Selvatici Rita, Falzarano Maria Sofia, Spedicato Noemi, Margutti Alice, Rimessi Paola, Fortunato Fernanda, Fabris Marina, Gualandi Francesca, Comi Giacomo, 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 Guia, Santorelli Filippo Maria, 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, Vita Giuseppe, 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
Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, Italy.
Front Genet. 2020 Mar 3;11:131. doi: 10.3389/fgene.2020.00131. eCollection 2020.
Dystrophinopathies are inherited diseases caused by mutations in the dystrophin () gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008-2017). In DMD patients, we found deletions 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 domain, with effects on population genetic characteristics and new personalized therapies.
肌营养不良蛋白病是由肌营养不良蛋白（）基因突变引起的遗传性疾病，对于其进行检测对于基因诊断、生殖选择以及参与个性化试验的资格来说是必不可少的。在一项为期10年（2008 - 2017年）、涉及11个诊断中心的全国性研究中，我们对意大利1902例患者（贝克型肌营养不良症患者740例，占39%；杜氏肌营养不良症患者1162例，占61%）的该基因进行了基因分型。在杜氏肌营养不良症患者中，我们发现57%为缺失突变，11%为重复突变，32%为小突变。在贝克型肌营养不良症患者中，我们发现78%为缺失突变，9%为重复突变，13%为小突变。在贝克型肌营养不良症中，缺失突变数量更多，小突变比重复突变更常见。在两种表型中通常都较为常见的小突变中，44%的杜氏肌营养不良症患者和36%的贝克型肌营养不良症患者为无义突变，因此有资格接受终止密码子通读疗法；所有移码缺失中有63%有资格接受单外显子跳跃治疗。患者还被分配到意大利各地区，并且在突变分布上呈现出有趣的地区差异。在这个大规模的全国性队列中的完整基因特征分析使我们能够得出杜氏肌营养不良症/贝克型肌营养不良症基因型图谱与突变频率、突变类型、基因上的突变位置、外显子/内含子结构以及相关蛋白结构域之间的若干相关性，这些相关性对群体遗传特征和新的个性化疗法产生影响。
