Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS

Objective: To identify the disease-causing gene of a family with upper limb predominant, slowly progressive amyotrophic lateral sclerosis (ALS), which was diagnosed as flail arm syndrome (FAS). Methods: After causation of 24 known ALS genes was excluded by targeted next-generation sequencing, whole-exome sequencing was applied in the FAS family. Cellular localization of mutant hnRNPA1 was examined in transfected HeLa cells. An additional 251 Chinese patients with ALS (including 7 sporadic FAS) underwent mutation screening of hnRNPA1. Results: We detected a novel missense mutation in hnRNPA1, c.862/1018C. T (p.P288S/P340S), which cosegregated with disease in the FAS family. The residue is highly conserved across species and exists in the encoded PY nuclear localization signal of hnRNPA1 protein. Mutant hnRNPA1 showed altered intracellular localization, resulting in formation of cytoplasmic inclusions that colocalized with stress granules in transfected cells. Further mutation screening of hnRNPA1 in additional patients with FAS and typical ALS detected 2 rare variants with unknown significance. These variants lie in the prion-like domain of hnRNPA1 long isoform, which was detected exclusively in the CNS. Conclusions: Our results suggest that hnRNPA1 is the causative gene in the family with flail arm ALS. This further expanded the disease phenotype of hnRNPA1 mutations.