Genotype–phenotype correlation ofSQSTM1variants in patients with amyotrophic lateral sclerosis

Abstract

BackgroundSeveral variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype–phenotype correlation remains unclear.MethodsWe screened variants ofSQSTM1gene in 2011 Chinese patients with ALS and performed a burden analysis focusing on the rare variants. Furthermore, we conducted a comprehensive analysis of patients with variants ofSQSTM1gene in patients with ALS from our cohort and published studies.ResultsIn our cohort, we identified 32 patients with 25 differentSQSTM1variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS withSQSTM1variant in our cohort had comorbid cognitive impairment and 43% (3/7) of them had behavioural variant frontotemporal dementia (FTD). Our meta-analysis found a total frequency ofSQSTM1variants in 7183 patients with ALS was 2.4%; burden analysis indicated that patients with ALS had enrichment of ultra-rare (minor allele frequency<0.01%) probably pathogenic variants inSQSTM1. Most variants were missense variants and distributed in various domains of p62 protein, some of which might be related to comorbidities of Paget’s disease of bone and FTD.ConclusionOur study established the largest cohort of patients with ALS withSQSTM1variants, expanded the mutation spectrum and investigated the genotype–phenotype correlations ofSQSTM1variants.