Department of Neurology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
Department of Clinical Laboratory, Peking University First Hospital, Beijing, 100034, China.
Orphanet J Rare Dis. 2024 Mar 14;19(1):123. doi: 10.1186/s13023-024-03128-7.
Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies.
Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them.
Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn't reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively.
Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.
在肌营养不良症（DMD）中，很少有报道称致病性错义变体存在于抗肌萎缩蛋白（Dystrophin，DMD）基因中。大多数 DMD 错义变体的意义不确定，其致病性解释仍然很复杂。我们旨在研究 DMD 错义变体是否会导致异常剪接，并根据 mRNA 和蛋白质研究重新解释其致病性。
我们招募了 9 名血清肌酸激酶水平升高伴或不伴肌肉无力的无关患者。他们接受了详细的临床、影像学和病理学评估。对他们进行了常规基因检测以及肌肉源性 Dystrophin 和 sarcoglycan 基因的 mRNA 和蛋白质研究。
9 名患者中有 3 名表现出杜氏肌营养不良症（Duchenne muscular dystrophy，DMD）表型，其余 6 名患者根据其临床和病理特征，疑似诊断为 Becker 肌营养不良症（Becker muscular dystrophy，BMD）或 sarcoglycanopathy。常规基因检测仅在他们中检测到 9 个预测的 DMD 错义变体，其中 6 个是新的，被解释为意义不确定。sarcoglycan 基因的肌肉源性 mRNA 研究未发现任何异常转录物。Dystrophin mRNA 研究证实，3 个预测的 DMD 错义变体（c.2380G > C、c.4977C > G 和 c.5444A > G）实际上是由于异常剪接而导致的剪接和移码变体。基于 mRNA 和蛋白质研究，这 9 个 DMD 变体被重新解释为致病性或可能致病性。因此，3 名患者被诊断为 DMD 剪接变体，6 名患者被诊断为 DMD 错义变体伴明确诊断为 BMD。
我们的研究强调了肌肉活检和异常剪接对于不确定的 DMD 错义变体的临床和遗传解释的重要性。
