Genotype-phenotype correlation of <i>SQSTM1</i> variants in patients with amyotrophic lateral sclerosis.

Abstract

Several variants of sequestosome 1 (<i>SQSTM1</i>) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype-phenotype correlation remains unclear. We screened variants of <i>SQSTM1</i> gene 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 of <i>SQSTM1</i> gene in patients with ALS from our cohort and published studies. In our cohort, we identified 32 patients with 25 different <i>SQSTM1</i> variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with <i>SQSTM1</i> variant 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 of <i>SQSTM1</i> variants 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 in <i>SQSTM1</i>. 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. Our study established the largest cohort of patients with ALS with <i>SQSTM1</i> variants, expanded the mutation spectrum and investigated the genotype-phenotype correlations of <i>SQSTM1</i> variants.