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Genotype-phenotype correlations
Original research
Genotype–phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis
  1. Shichan Wang,
  2. Qirui Jiang,
  3. Xiaoting Zheng,
  4. Qianqian Wei,
  5. Junyu Lin,
  6. Tianmi Yang,
  7. Yi Xiao,
  8. Chunyu Li,
  9. Huifang Shang
  1. Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  1. Correspondence to Professor Huifang Shang, Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China; hfshang2002{at}126.com; Professor Chunyu Li, Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China; lichunyu.scu{at}qq.com

Abstract

Background Several variants of sequestosome 1 (SQSTM1) were screened in patients with amyotrophic lateral sclerosis (ALS), while the pathogenicity and genotype–phenotype correlation remains unclear.

Methods We screened variants of SQSTM1 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 SQSTM1 gene in patients with ALS from our cohort and published studies.

Results In our cohort, we identified 32 patients with 25 different SQSTM1 variants with a mutant frequency of 1.6%. Notably, 26% (5/19) of the patients with ALS with SQSTM1 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 SQSTM1 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 SQSTM1. 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.

Conclusion Our study established the largest cohort of patients with ALS with SQSTM1 variants, expanded the mutation spectrum and investigated the genotype–phenotype correlations of SQSTM1 variants.

  • Neurodegenerative Diseases

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The genotype and phenotype data of the Taiwanese Schizophrenia Trio Collection were applied from dbGap (accession number phs001196.v1.p1). Data analysed during this study are included in tables and supplementary materials.

https://doi.org/10.1136/jmg-2023-109569

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The genotype and phenotype data of the Taiwanese Schizophrenia Trio Collection were applied from dbGap (accession number phs001196.v1.p1). Data analysed during this study are included in tables and supplementary materials.

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    Footnotes

    • Presented at This work was previously presented as an abstract at the 34th International Symposium on ALS/MND, December 2023 (Wang S, Jiang Q, Zheng X, et al. Genotype-­phenotype correlation of SQSTM1 variants in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and ­Frontotemporal ­Degeneration ­2023;­24(sup1):­99– ­114. doi:­ 10.1080/­21678421.­2023.­2260192).

    • Contributors SW contributed to the conception and design of the study, acquisition and analysis of data, drafting the text and preparing the figures. QJ, XZ and J-YL contributed to blood samples collection and DNA extraction. QW, TY and YX contributed to the patients enrolment and clinical data collection. C-YL and HS contributed to the conception and design of the study, acquisition and analysis of data and revising the manuscript. HS is the guarantor responsible for the integrity of the work, the conduct of the study and the decision to publish.

    • Funding This work was supported by the Sichuan Science and Technology Program (Grant No. 2022ZDZX0023).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.