PDF(Pubmed)
Abstract：
DMD gene pathogenic variations cause a spectrum of phenotypes, ranging from severe Duchenne muscular dystrophy, the Becker milder cases, the intermediate or very mild muscle phenotypes invariably characterized by high CK, and the ultrarare fully-asymptomatic cases. Besides these phenotypes, X-linked dilated cardiomyopathy is also caused by DMD mutations. Males carrying DMD deletions with absent or very mild phenotypes have been sparsely described. We performed a horizon scan on public datasets to enroll males with the above phenotypes and carrying DMD deletions to delineate myopathic genotype-phenotype relationships. We inventoried 81 males, who were divided into the following clinical categorization: fully-asymptomatic males aged >43 years (A, N = 22); isolated hyperCKemia (CK, N = 35); and mild weakness (any age) with or without high CK (WCK, N = 24). In all cases, deleted intervals were exons 2 to 55, and no downstream exons were ever involved, apart from an exon 78 deletion in a WCK patient. All deletions were in-frame apart from the known exception to the rule of exon 2 and exon 78. We correlated the mild phenotypes (A and CK) to deleted exons, intronic breakpoints, exon-exon junctions, 3\' isoforms rule, and protein epitopes, and we found that some genetic profiles are exclusively/mainly occurring in A/CK phenotypes, suggesting they are compatible with a quasi-normal muscular performance. We discussed diverse pathogenic mechanisms that may contribute to mild dystrophinopathic phenotypes, and we tried to address some \"critical\" genetic configurations or exon content needed to preserve a semi-functional DMD gene.
摘要：
DMD基因致病变异引起一系列表型，严重的杜氏肌营养不良症，贝克尔温和的案子，中等或非常温和的肌肉表型总是以高CK为特征，和超异常完全无症状病例。除了这些表型,X连锁扩张型心肌病也是由DMD突变引起的。携带DMD缺失且表型缺失或非常温和的雄性已被稀疏地描述。我们对公共数据集进行了地平线扫描，以招募具有上述表型并携带DMD缺失的男性，以描绘肌病基因型-表型关系。我们清点了81只雄性,他们分为以下临床分类：年龄>43岁的完全无症状男性(A，N=22)；孤立性高CKD(CK，N=35）；轻度虚弱（任何年龄），有或没有高CK（WCK，N=24）。在所有情况下,缺失的间隔是外显子2到55，没有下游外显子参与，除了WCK患者的外显子78缺失。除外显子2和外显子78规则的已知例外外，所有缺失均在框架内。我们将轻度表型（A和CK）与缺失的外显子相关联，内含子断点，外显子-外显子连接,3\'同工型规则，和蛋白质表位，我们发现一些基因谱完全/主要发生在A/CK表型中，表明它们与准正常的肌肉表现相容。我们讨论了不同的致病机制，可能有助于轻度肌萎缩症的表型，我们试图解决保存半功能性DMD基因所需的一些“关键”遗传构型或外显子内容。
