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The prognostic value of systematic genetic screening in amyotrophic lateral sclerosis patients

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Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with complex genetic architecture. Emerging evidence has indicated comorbidity between ALS and autoimmune conditions, suggesting a potential shared genetic basis. The objective of this study is to assess the prognostic value of systematic screening for rare deleterious mutations in genes associated with ALS and aberrant inflammatory responses.

Methods

A discovery cohort of 494 patients and a validation cohort of 69 patients were analyzed in this study, with population-matched healthy subjects (n = 4961) served as controls. Whole exome sequencing (WES) was performed to identify rare deleterious variants in 50 ALS genes and 1177 genes associated with abnormal inflammatory responses. Genotype–phenotype correlation was assessed, and an integrative prognostic model incorporating genetic and clinical factors was constructed.

Results

In the discovery cohort, 8.1% of patients carried confirmed ALS variants, and an additional 15.2% of patients carried novel ALS variants. Gene burden analysis revealed 303 immune-implicated genes with enriched rare variants, and 13.4% of patients harbored rare deleterious variants in these genes. Patients with ALS variants exhibited a more rapid disease progression (HR 2.87 [95% CI 2.03–4.07], p < 0.0001), while no significant effect was observed for immune-implicated variants. The nomogram model incorporating genetic and clinical information demonstrated improved accuracy in predicting disease outcomes (C-index, 0.749).

Conclusion

Our findings enhance the comprehension of the genetic basis of ALS within the Chinese population. It also appears that rare deleterious mutations occurring in immune-implicated genes exert minimal influence on the clinical trajectories of ALS patients.

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Data availability

The summary of genetic alterations in ALS patients analyzed during this study is included in the supplementary files and deposited in the Genome Variation Map (GVM) in National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, under accession number GVM000588. Individual-level sequencing data are available from the corresponding authors on reasonable request.

Abbreviations

ACMG:

American College of Medical Genetics and Genomics

ALS:

Amyotrophic lateral sclerosis

ALS-MiToS:

Milano-Torino Staging for Amyotrophic Lateral Sclerosis

ALSFRS-R:

ALS Functional Rating Scale–Revised

BMI:

Body mass index

cGAS-STING:

Cyclic GMP-AMP synthase-stimulator of interferon genes

CI:

Confidence interval

ENCALS:

European Network for the Cure of ALS

fALS:

Familial ALS

FTD:

Frontotemporal dementia

GATK:

Genome analysis toolkits

HR:

Hazard ratio

MAF:

Minor allele frequency

PUMCH:

Peking Union Medical College Hospital

ROADS:

Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale

sALS:

Sporadic ALS

VUS:

Variants of unknown significance

WES:

Whole exome sequencing

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Acknowledgements

The authors acknowledge the kind support from the patients and their families for their participation in this study. They also thank Beijing Grandomics Biosciences Co Ltd. for coding support.

Funding

This work was supported by the Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (Grant number: XDB39040000), CAMS Innovation Fund for Medical Sciences (2021-I2M-1–003, 2019-I2M-5-066), National Science Foundation of China (32288101, 32200536, 82371431), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and 2020 Medical Service and Support Capacity Improvement Project: Construction of the Cohort-Based Multidisciplinary Accurate Diagnosis and Treatment Platform for Neurological Autoimmune and Infectious Diseases.

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Author notes

  1. Di He, Yining Liu, Siqi Dong and Dongchao Shen have contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Neurology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Dongcheng District, Beijing, China

    Di He, Dongchao Shen, Xunzhe Yang, Mingsheng Liu & Liying Cui

  2. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China

    Yining Liu, Meng Hao, Xianhong Yin, Xinyi He, Yi Li, Yi Wang & Jiucun Wang

  3. Department of Neurology, Huashan Hospital and Institute of Neurology, National Center for Neurological Disorders, Fudan University, Shanghai, China

    Siqi Dong & Xiangjun Chen

  4. Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China

    Jiucun Wang & Xiangjun Chen

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Contributions

DH and LC: contributed to study concept and design. All the authors performed acquisition, analysis, or interpretation of data. DH: drafted the manuscript. All the authors were involved in critical revision of the manuscript for important intellectual content. DH, YL, and SD: performed statistical analysis. LC, XC, and JW obtained funding. LC, XC, and JW: supervised the study.

Corresponding authors

Correspondence to Jiucun Wang, Xiangjun Chen or Liying Cui.

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Conflict of interest

There is no conflict of interest to be disclosed.

Ethical approval and consent to participate

Ethical approval for this study was obtained from the PUMCH Research Ethical Boards (No. JS-2624). All participants have provided written consent or given permission for a relative to sign on their behalf.

Declaration of generative AI and AI-assisted technologies in the writing process

No generative AI or AI-assisted technologies have been used in the writing process.

Supplementary Information

Below is the link to the electronic supplementary material.

415_2023_12079_MOESM1_ESM.xlsx

Supplementary Table S1. ALS-implicated gene panel (HP:0007354). Table S2. Immune-implicated gene panel (HP:0012647). Table S3. List of identified rare deleterious ALS variants in the discovery cohort. Table S4. List of immune-implicated genes with enriched rare variants by SKAT analysis after Bonferroni correction. Table S5. List of identified rare deleterious immune variants in the discovery cohort. Table S6. List of identified rare deleterious immune variants in the validation cohort. Table S7. List of identified rare deleterious immune variants in the validation cohort. file1 (XLSX 2651 KB)

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He, D., Liu, Y., Dong, S. et al. The prognostic value of systematic genetic screening in amyotrophic lateral sclerosis patients. J Neurol 271, 1385–1396 (2024). https://doi.org/10.1007/s00415-023-12079-1

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