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

Amyotrophic lateral sclerosis (ALS) is anadult-onsetneurodegenerative disease characterizedby lossofmotor 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 1-3novelvariants of uncertainsignificance, whereas hexanucleotide repeat expansions inC9ORF72 were not detected using repeat-primed polymerase chain reaction. Collectively, in our Japanese cohort, the frequencies of SOD1, FUS, SETX, TARDBP, ANG, and OPTNvariantswere 32%, 11%, 2%, 2%, 1%, and 1%, respectively. These findings indicate considerable differences in the genetic variations associatedwith familial ALS across populations. Further genetic analyses and functional studies of novel variants are warranted. (C) 2017 Elsevier Inc. All rights reserved.