Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
Neuromuscul Disord. 2014 Jul;24(7):642-7. doi: 10.1016/j.nmd.2014.04.002. Epub 2014 Apr 24.
When an expected mutation in a particular disease-causing gene is not identified in a suspected carrier, it is usually assumed to be due to germline mosaicism. We report here very-low-grade somatic mosaicism in ACTA1 in an unaffected mother of two siblings affected with a neonatal form of nemaline myopathy. The mosaicism was detected by deep resequencing using a next-generation sequencer. We identified a novel heterozygous mutation in ACTA1, c.448A>G (p.Thr150Ala), in the affected siblings. Three-dimensional structural modeling suggested that this mutation may affect polymerization and/or actin's interactions with other proteins. In this family, we expected autosomal dominant inheritance with either parent demonstrating germline or somatic mosaicism. Sanger sequencing identified no mutation. However, further deep resequencing of this mutation on a next-generation sequencer identified very-low-grade somatic mosaicism in the mother: 0.4%, 1.1%, and 8.3% in the saliva, blood leukocytes, and nails, respectively. Our study demonstrates the possibility of very-low-grade somatic mosaicism in suspected carriers, rather than germline mosaicism.
当在疑似携带者中未发现特定致病基因突变时，通常假定是由于种系嵌合体。我们在此报告了一例 2 名受累同胞的新生儿型肌营养不良症的无影响母亲中存在非常低水平的 ACTA1 体细胞嵌合体。通过使用下一代测序仪进行深度重测序检测到了嵌合体。我们在受累的同胞中发现了 ACTA1 中的一个新的杂合突变，c.448A>G (p.Thr150Ala)。三维结构建模表明该突变可能影响聚合和/或肌动蛋白与其他蛋白质的相互作用。在这个家庭中，我们预计常染色体显性遗传，父母一方表现为种系或体细胞嵌合体。桑格测序未发现突变。然而，对该突变在下一代测序仪上的进一步深度重测序在母亲中发现了非常低水平的体细胞嵌合体：唾液、血液白细胞和指甲中的分别为 0.4%、1.1%和 8.3%。我们的研究表明，疑似携带者中存在非常低水平的体细胞嵌合体的可能性，而不是种系嵌合体。
