Deep sequencing detects very-low-grade somatic mosaicism in the unaffected mother of siblings with nemaline myopathy.
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.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Satoko
S
Miyatake
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Eriko
E
Koshimizu
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
Yukiko K
YK
Hayashi
Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan.
Kazushi
K
Miya
Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Masaaki
M
Shiina
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Mitsuko
M
Nakashima
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yoshinori
Y
Tsurusaki
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Noriko
N
Miyake
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Hirotomo
H
Saitsu
Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kazuhiro
K
Ogata
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Ichizo
I
Nishino
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: naomat@yokohama-cu.ac.jp.
Naomichi
N
Matsumoto
D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005220:Fathers; D005260:Female; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009030:Mosaicism; D009035:Mothers; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D035781:Siblings
ACTA1; Deep resequencing; Low-grade somatic mosaicism; Nemaline myopathy; Next-generation sequencer