Comprehensive targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis

Publication date: Available online 10 January 2017
Source:Neurobiology of Aging
Author(s): Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki
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 (MNDs)-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 one patient. Additionally, 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.



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