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Neuromuscul Disord. 2014 Jul;24(7):642-7. doi: 10.1016/j.nmd.2014.04.002. Epub 2014 Apr 24.

Deep sequencing detects very-low-grade somatic mosaicism in the unaffected mother of siblings with nemaline myopathy.

Author information

  • 1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 2Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
  • 3Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan.
  • 4Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 5Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 6Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: naomat@yokohama-cu.ac.jp.

Abstract

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.

KEYWORDS:

ACTA1; Deep resequencing; Low-grade somatic mosaicism; Nemaline myopathy; Next-generation sequencer

PMID:
24852243
DOI:
10.1016/j.nmd.2014.04.002
[PubMed - indexed for MEDLINE]
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