肌营养不良蛋白
基因检测
RNA剪接
医学
计算生物学
生物信息学
外显子
基因
遗传学
病理
生物
生物信息学
核糖核酸
作者
Zhiying Xie,Chengyue Sun,Yilin Liu,Meng Yu,Yiming Zheng,Lingchao Meng,Gao Wang,Diana M. Cornejo-Sanchez,Thashi Bharadwaj,Yan Jin,Lingxiang Zhang,Nicolás Pineda-Trujillo,Shouxin Zhang,Suzanne M. Leal,Isabelle Schrauwen,Zhaoxia Wang,Yun Yuan
标识
DOI:10.1136/jmedgenet-2020-107113
摘要
To investigate the diagnostic value of implementing a stepwise genetic testing strategy (SGTS) in genetically unsolved cases with dystrophinopathies.After routine genetic testing in 872 male patients with highly suspected dystrophinopathies, we identified 715 patients with a pathogenic DMD variant. Of the 157 patients who had no pathogenic DMD variants and underwent a muscle biopsy, 142 patients were confirmed to have other myopathies, and 15 suspected dystrophinopathies remained genetically undiagnosed. These 15 patients underwent a more comprehensive evaluation as part of the SGTS pipeline, which included the stepwise analysis of dystrophin mRNA, short-read whole-gene DMD sequencing, long-read whole-gene DMD sequencing and in silico bioinformatic analyses.SGTS successfully yielded a molecular diagnosis of dystrophinopathy in 11 of the 15 genetically unsolved cases. We identified 8 intronic and 2 complex structural variants (SVs) leading to aberrant splicing in 10 of 11 patients, of which 9 variants were novel. In one case, a molecular defect was detected on mRNA and protein level only. Aberrant splicing mechanisms included 6 pseudoexon inclusions and 4 alterations of splice sites and splicing regulatory elements. We showed for the first time the exonisation of a MER48 element as a novel pathogenic mechanism in dystrophinopathies.Our study highlights the high diagnostic utility of implementing a SGTS pipeline in dystrophinopathies with intronic variants and complex SVs.
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