Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Children's Hospital of Eastern Ontario Research Institute, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
J Neuromuscul Dis. 2021;8(4):525-535. doi: 10.3233/JND-210658.
Duchenne muscular dystrophy (DMD) is an X-linked disorder caused due to large deletions, duplications,and small pathogenic variants. This article compares the carrier frequency of different pathogenic variants in the DMD gene for the first time in an Indian cohort.
Ninety-one mothers of genetically confirmed DMD probands are included in this study. Pathogenic variants in the DMD gene in probands were detected by multiplex ligation-dependent probe amplification (MLPA) or next-generation sequencing (NGS). Maternal blood samples were evaluated either by MLPA or Sanger sequencing. The demographic and clinical details for screening of muscle weakness and cardiomyopathy were collected from the confirmed carriers.
Out of 91 probands, large deletions and duplications were identified in 46 and 6 respectively, while 39 had small variants. Among the small variants, substitutions predicted to cause nonsense mutations were the most common (61.5%), followed by frameshift causing small insertion/deletions (25.6%) and splice affecting intronic variants (12.8%). Notably, 19 novel small variants predicted to be disease-causing were identified. Of the 91 mothers, 53 (58.7%) were confirmed to be carriers. Exonic deletions had a significantly lower carrier frequency of 47.8% as compared to small variants (64.1%). The mean age of the carriers at evaluation was 30 years. Among the carriers, two were symptomatic with onset in the 4th decade, manifesting with progressive proximal muscle weakness and dilated cardiomyopathy.
Carrier frequency of small pathogenic variants differs significantly from large deletions. Small pathogenic variants are more commonly inherited, whereas large deletions arise de novo.
杜氏肌营养不良症（DMD）是一种 X 连锁疾病，由大片段缺失、重复和小的致病性变异引起。本文首次在印度队列中比较了 DMD 基因中不同致病性变异的携带频率。
本研究纳入了 91 名经基因确诊的 DMD 先证者的母亲。先证者的 DMD 基因中的致病性变异通过多重连接依赖性探针扩增（MLPA）或下一代测序（NGS）进行检测。通过 MLPA 或 Sanger 测序评估母亲的血液样本。从确诊的携带者中收集筛查肌肉无力和心肌病的人口统计学和临床详细信息。
在 91 名先证者中，46 名存在大片段缺失和重复，6 名存在重复，39 名存在小变异。在小变异中，预测导致无义突变的取代是最常见的（61.5%），其次是导致小插入/缺失的移码（25.6%）和影响内含子的剪接变异（12.8%）。值得注意的是，发现了 19 种新的预测为致病的小变异。在 91 位母亲中，53 位（58.7%）被确认为携带者。外显子缺失的携带频率明显低于小变异（47.8%）（64.1%）。携带者评估时的平均年龄为 30 岁。在携带者中，有两名在 40 岁时出现症状，表现为进行性近端肌肉无力和扩张型心肌病。
小致病性变异的携带频率与大片段缺失有显著差异。小致病性变异更常遗传，而大片段缺失是新生的。
