Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
Department of Rehabilitation Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Mol Genet Genomic Med. 2019 Aug;7(8):e866. doi: 10.1002/mgg3.866. Epub 2019 Jul 22.
Early-onset myopathies show a wide spectrum of phenotypes and are composed of various types of inherited neuromuscular diseases, making it difficult to diagnose. TTN mutation-related myopathy is a known cause of early-onset myopathy. Since a next-generation sequencing (NGS) has enabled sequencing of the vast amount of DNA, TTN, which is the longest coding sequence of any human gene, mutations can now be revealed. We report a 10-year-old female with severe congenital muscular weakness and delayed motor development since birth.
Next-generation sequencing as well as electromyography and muscle biopsy were performed.
To date, she is incapable of walking alone. Her younger sister had similar but more severe symptoms with respiratory failure. In electromyography, short-duration, small-amplitude motor unit action potential, and early recruitment patterns were observed in the involved proximal muscles, suggesting myopathy. Muscle histopathology showed a specific atrophy of increased fiber size variability, frequent nuclear internalization, as well as degeneration and regeneration of fibers with type I fiber predominance, consistent with the findings of a previous report about congenital titinopathy. A NGS study revealed two different possible pathogenic variants in TTN: (a) canonical splicing mutation in the intron 105 (c. 29963-1G>C) and (b) frameshift and truncating mutation in the exon 339 (c.92812dup/p.Arg30938LysfsTer15). All variants were confirmed by conventional Sanger sequencing.
We propose that unbiased genomic sequencing can be helpful in screening patients with early-onset myopathy.
早发性肌病表现出广泛的表型谱，由各种类型的遗传性神经肌肉疾病组成，因此难以诊断。TTN 突变相关肌病是早发性肌病的已知病因。由于下一代测序（NGS）能够对大量 DNA 进行测序，现在可以揭示 TTN 的突变，TTN 是人类基因中最长的编码序列。我们报告了一例 10 岁女性，自出生以来即存在严重的先天性肌肉无力和运动发育迟缓。
进行了下一代测序以及肌电图和肌肉活检。
迄今为止，她还不能独自行走。她的妹妹有类似但更严重的症状，伴有呼吸衰竭。在肌电图中，受累的近端肌肉中观察到短时限、小幅度运动单位动作电位和早期募集模式，提示肌病。肌肉组织病理学显示纤维大小变异性增加、核内移以及纤维变性和再生的特定萎缩，伴有Ⅰ型纤维优势，与先前关于先天性肌联蛋白病的报告结果一致。NGS 研究发现 TTN 中有两种不同的可能致病性变异：（a）内含子 105 中的经典剪接突变（c.29963-1G>C）和（b）外显子 339 中的框移和截断突变（c.92812dup/p.Arg30938LysfsTer15）。所有变异均通过常规 Sanger 测序得到确认。
我们提出，无偏基因组测序有助于筛查早发性肌病患者。
