The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Pediatric Neurology Unit, Faculty of Health Sciences, Soroka Medical Center, Joyce and Irving Goldman Medical School, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Mol Diagn Ther. 2022 Sep;26(5):561-568. doi: 10.1007/s40291-022-00601-6. Epub 2022 Jul 7.
Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia.
Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies.
We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript.
This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.
先天性肌病是一组由多种遗传因素引起的先天性肌肉疾病，常表现为肌肉萎缩和低张力。
临床研究、影像学、组织学、全外显子组测序（WES）和肌肉组织 RNA 研究。
我们描述了一种严重的先天性肌病，出生时即表现为双侧马蹄内翻足、运动发育迟缓伴低张力，4 个月时明显。3 岁时，患者出现舌肌束颤，卧床不起，长期通过气管造口进行通气。影像学研究显示严重的肌肉萎缩，令人惊讶的是还有大脑萎缩；肌电图显示肌无力模式，组织学评估无法明确诊断。对先证者及其父母的 trio-WES 未发现致病突变，仅在 TPM3 基因上发现一个非 canonical 内含子 c.118-12G>A 杂合变异，意义未明。对患者肌肉组织的转录分析证实了该纯合变异的致病性，导致肌肉特异性 TPM3.12 转录本减少了 97%。
本研究拓宽了 TPM3 隐性疾病的表型谱，突出了舌肌束颤和双侧马蹄内翻足，以及可能相关的大脑萎缩。它还表明了广泛的遗传分析方法和基于 RNA 的研究的重要性，证明了早期基因组和转录组查询在促进先天性肌病的快速和具有成本效益的诊断方面的有效性。
