Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients. A novel likely pathogenic homozygous variant in ALS2 was identified in 1 patient. In addition, 18 patients harbored 1-3 novel variants of uncertain significance, whereas hexanucleotide repeat expansions in C9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTN variants were 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associated with familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted.
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Ayumi
A
Nishiyama
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Tetsuya
T
Niihori
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Hitoshi
H
Warita
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Rumiko
R
Izumi
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Tetsuya
T
Akiyama
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Masaaki
M
Kato
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Naoki
N
Suzuki
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
Yoko
Y
Aoki
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: aokim@med.tohoku.ac.jp.
Masashi
M
Aoki
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D000073885:C9orf72 Protein / Q000235:genetics; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods* / Q000639:trends*; D006801:Humans; D026901:Membrane Transport Proteins; D064251:Multifunctional Enzymes; D020365:RNA Helicases / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics; D012259:Ribonuclease, Pancreatic / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D035582:Transcription Factor TFIIIA / Q000235:genetics
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000599550:FUS protein, human; D026901:Membrane Transport Proteins; D064251:Multifunctional Enzymes; C409460:OPTN protein, human; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; C000598624:TARDBP protein, human; D035582:Transcription Factor TFIIIA; D000072105:Superoxide Dismutase-1; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
Familial amyotrophic lateral sclerosis; Genetic analysis; Japanese; Next-generation sequencer