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Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity. Recent studies have suggested an oligogenic basis of ALS, in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects. To assess the contribution of possible oligogenic inheritance, we profiled a panel of 43 relevant genes in 57 sporadic ALS (sALS) patients and eight familial ALS (fALS) patients from five pedigrees in east China. We filtered rare variants using the combination of the Exome Aggregation Consortium, the 1000 Genomes and the HuaBiao Project. We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype correlation. Overall, we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes, among which two sALS and four fALS patients harbored two or more variants. Of note, the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants. Typically, in one fALS pedigree with three variants, the family member with three variants (Superoxide dismutase 1 (SOD1) p.V48A,  Optineurin (OPTN) p.A433V and TANK binding kinase 1 (TBK1) p.R573H) exhibited much more severe disease phenotype than the member carrying one variant (TBK1 p.R573H). Our findings suggest that rare variants could exert a negative prognostic effect, thereby supporting the oligogenic inheritance of ALS.

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Data Availability

The datasets generated from the statistical analyses during the current study are available from the corresponding author on reasonable request.

Abbreviations

ACMG:

The American College of Medical Genetics and Genomics

ALS:

Amyotrophic lateral sclerosis

ALS2:

Amyotrophic lateral sclerosis 2

ALSdb:

ALS data browser

ALSod:

Amyotrophic Lateral Sclerosis online Database

ANG:

Angiogenin

ANXA11:

Annexin A11

ATXN2:

Ataxin 2

C9orf72:

Chromosome 9 open reading frame 72

C21orf2:

Cilia- and flagella-associated protein 410

CAMTA1:

Calmodulin-binding transcription activator 1

CCNF:

Cyclin F

CHCHD10:

Coiled-coil-helix-coiled-coil-helix domain containing 10

CHMP2B:

Charged multivesicular body protein 2B

CYLD:

Cylindromatosis

DCTN1:

Dynactin subunit 1

DNAJC7:

DnaJ heat shock protein family (Hsp40) member C7

ELP3:

Elongator acetyltransferase complex subunit 3

EPHA4:

Ephrin type-A receptor 4

ERBB4:

Erb-B2 receptor tyrosine kinase 4

ExAC:

The Exome Aggregation Consortium

fALS:

Familial amyotrophic lateral sclerosis

FTD:

Frontotemporal dementia

FIG4:

FIG4 phosphoinositide 5-phosphatase

FUS:

Fused in sarcoma

GLT8D1:

Glycosyltransferase 8 domain containing 1

HNRNPA1:

Heterogeneous nuclear ribonucleoprotein A1

HNRNPA2B1:

Heterogeneous nuclear ribonucleoprotein A2/B1

KIF5A:

Kinesin family member 5A

LGALSL:

Lectin galactoside-binding-like protein

MATR3:

Matrin 3

NEFH:

Neurofilament heavy chain

NEK1:

NIMA-related kinase 1

OMIM:

Online Mendelian inheritance in man

OPTN:

Optineurin

PFN1:

Profilin 1

PRPH:

Peripherin

sALS:

Sporadic amyotrophic lateral sclerosis

SETX:

Senataxin

SIGMAR1:

Sigma non-opioid intracellular receptor 1

SNP:

Single-nucleotide polymorphisms

SOD1:

Superoxide dismutase 1

SPG11:

Spastic paraplegia 11

SPTLC1:

Serine palmitoyltransferase long chain base subunit 1

SQSTM1:

Sequestosome 1

TARDBP:

TAR DNA-binding protein

TBK1:

TANK-binding kinase 1

TIA1:

Cytotoxic granule-associated RNA-binding protein

TUBA4A:

Tubulin Alpha 4a

UBQLN2:

Ubiquilin 2

UNC13A:

Unc-13 Homolog A

VAPB:

Vesicle-associated membrane protein-associated protein B/C

VCP:

Valosin-containing protein

WES:

Whole-exome sequencing

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Acknowledgements

The authors would like to give their gratitude to all the study participants and their families for their dedication to ALS research. The authors would like to thank HuaBiao Project: Whole-Exome Database of Han Chinese, for we use the database as control.

Funding

This work was supported by 2020 Central Transfer Payment Medical Siege Institutions Capacity Building Project (National and Provincial Multi-scientific Cooperation Diagnosis and Treatment of Major Diseases Capacity Building Project); Shanghai Fudan University Education Development Foundation and State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University; Shanghai Municipal Science and Technology Major Project 2017HZDZX01.

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  1. Siqi Dong and Xianhong Yin have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, 200040, China

    Siqi Dong, Wenbo Yang, Jiatong Li, Xiaoni Liu & Xiangjun Chen

  2. National Center for Neurological Disorders, Shanghai, 200040, China

    Siqi Dong, Wenbo Yang, Jiatong Li, Xiaoni Liu & Xiangjun Chen

  3. Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Xianhong Yin, Kun Wang, Yi Wang, Yanni Zhou & Jiucun Wang

  4. Human Phenome Institute, Fudan University, Shanghai, 200433, China

    Xianhong Yin, Yi Wang, Jiucun Wang & Xiangjun Chen

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  1. Siqi Dong
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Contributions

Included conception and study design (XC and JW), data collection or acquisition (SD, XY, KW, WY, JL, YZ and XL), statistical analysis (SD, XY, KW and YW), interpretation of results (SD, XY, KW, JW and XC), drafting the manuscript work (SD, XY, JW and XC) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (all the authors).

Corresponding authors

Correspondence to Jiucun Wang or Xiangjun Chen.

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The studies involving human participants were reviewed and approved by the Ethics Committee of Huashan Hospital, Fudan University. The patients/participants provided their written informed consent to participate in this study.

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Dong, S., Yin, X., Wang, K. et al. Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis. Phenomics 3, 167–181 (2023). https://doi.org/10.1007/s43657-022-00093-8

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