Identification of a novel Cys146X mutation of SOD1 in familial amyotrophic lateral sclerosis by whole-exome sequencing.

Purpose: Familial amyotrophic lateral sclerosis has been linked to mutations in 15 genes, and it is believed these genes account for less than 20-30% of Chinese patients with familial amyotrophic lateral sclerosis. Of the 163 different superoxide dismutase 1 gene mutations in amyotrophic lateral sclerosis 1, only 6.1% of them were from individuals of Chinese origin. Therefore, to quickly learn the causative gene for patients with familial amyotrophic lateral sclerosis in a Chinese pedigree, we opted to apply whole-exome sequencing as a diagnostic tool.

Methods: To avoid time-consuming screening of known familial amyotrophic lateral sclerosis candidate genes by PCR-Sanger sequencing, we conducted whole-exome sequencing toward selected individuals of a four-generation familial amyotrophic lateral sclerosis family.

Results: Patients in the family showed autosomal dominant features, as well as a mean onset age of 35.3 years, and a mean duration of 2.1 years. By deep sequencing analysis, we identified a novel p.Cys146X SOD1 mutation in all examined patients. Genotype-phenotype and SOD1 structural model analysis revealed the effects of the Cys57-Cys146 disulfide bond formation and the C-terminal dimer contact region on the disease phenotypes.

Conclusion: The Cys146X mutation causes familial amyotrophic lateral sclerosis with severe phenotypes. Whole-exome sequencing becomes an attractive diagnostic tool for identifying causative genes, particularly for neurological disorders with unusual phenotypes, pleiotropic malformations, multiple known candidate genes, and complicated inheritance patterns.