As structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 (SQSTM1).

A candidate insertion/deletion variant within intron 5 of the SQSTM1 gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR.

A reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence SQSTM1 transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the SQSTM1 variant is associated with fALS (p = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients (p = 0.0005), but not with patients with sALS (p = 0.97).

This disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development.

由于结构变异可能是对复杂神经退行性疾病（例如肌萎缩侧索硬化症 (ALS) 的易感性）的基础，因此本研究的目的是研究隔离体 1 ( SQSTM1 ) 内的结构变异 (SV )。

使用先前建立的 SV 评估算法识别SQSTM1基因的内含子 5 内的候选插入/缺失变体，并根据其随后对基因表达的理论影响进行选择。通过 PCR、聚丙烯酰胺凝胶分级分离、Sanger 测序和逆转录酶 PCR 系统地评估了该变体。

可靠且稳健的测定证实了该变体的多态性，并且该变体可能影响SQSTM1转录水平。在北美家族性 ALS (fALS) 和散发性 ALS (sALS) (n = 403) 和年龄匹配的健康对照 (n = 562) 患者队列中，我们随后发现SQSTM1变体与 fALS ( p = 0.0036），特别是在家族性超氧化物歧化酶 1 突变阳性患者中（p = 0.0005），但在 sALS 患者中则不然（p = 0.97）。

这种疾病关联强调了进一步研究 SV 的重要性和意义，这可能为队列分层和治疗开发提供新的目标。