Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 May 21:17:1584541.
doi: 10.3389/fnagi.2025.1584541. eCollection 2025.

Genetic analysis of ERBB4 gene in Chinese patients with amyotrophic lateral sclerosis: a single-center study and systematic review of published literature

Dongchao Shen  1 , Xunzhe Yang  1 , Di He  1 , Kang Zhang  1 , Shuangwu Liu  1 , Xiaohan Sun  1 , Jinyue Li  1 , Zhengyi Cai  1 , Mingsheng Liu  1 , Xue Zhang  2 , Qing Liu  1   2 , Liying Cui  1   3
Affiliations

Genetic analysis of ERBB4 gene in Chinese patients with amyotrophic lateral sclerosis: a single-center study and systematic review of published literature

Dongchao Shen et al. Front Aging Neurosci. .

Abstract

Background: Rare ERBB4 variants have been implicated in amyotrophic lateral sclerosis (ALS), but their prevalence and clinical significance remain poorly understood, particularly across different ethnic populations.

Methods: We performed genetic screening of ERBB4 in 1627 Chinese ALS patients using whole-exome sequencing. A systematic review and meta-analysis of the published literature were conducted to evaluate the global frequency of ERBB4 variants and their clinical correlations.

Results: We identified 14 missense variants and 6 splice region variants in 23 unrelated patients, with four variants classified as damaging (p.R782P, p.M799T, p.R847C, and p.S997R). The splice variant c.1490-3C > T, associated with a 50% reduction in ERBB4 mRNA expression, was maternally inherited by a male ALS patient, while its presence in his asymptomatic mother suggests the involvement of potential genetic modifiers. ERBB4 variant carriers demonstrated earlier disease onset compared to non-carriers (46.9 ± 10.3 vs. 52.6 ± 11.2 years; p = 0.015), though survival duration remained comparable. Meta-analysis revealed a pooled ERBB4 variant frequency of 0.83% (95% CI, 0.56-1.10%) in ALS patients globally, with notable ethnic differences (1.36% in Chinese, 0.66% in European, and 1.44% in American populations).

Conclusion: Our findings establish the prevalence of ERBB4 variants in ALS across different populations and suggest their potential role as disease modifiers, particularly affecting the age of onset. The ethnic variation in mutation frequency highlights the importance of population-specific genetic screening strategies in ALS.

Keywords: ERBB4 variants; amyotrophic lateral sclerosis; disease modifiers; ethnic differences; genetic screening.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The flow chart of the literature search in the systematic review.
Figure 2
Figure 2
Meta-analysis of ERBB4 variant frequency in ALS patients. (A) Forest plot. (B) Leave-one-out analysis.
Figure 3
Figure 3
Forest plot of studies reporting ERBB4 variants in ALS in Chinese, European and American.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Adashek J. J., Pandya C., Maragakis N. J., De P., Cohen P. R., Kato S., et al. . (2024). Neuregulin-1 and als19 (erbb4): at the crossroads of amyotrophic lateral sclerosis and cancer. BMC Med. 22:74. doi: 10.1186/s12916-024-03293-3, PMID: - DOI - PMC - PubMed
    1. Al K. A., Iacoangeli A., van Vugt J., Bowles H., Moisse M., Zwamborn R., et al. . (2022). Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis. NPJ Genom. Med. 7:8. doi: 10.1038/s41525-021-00267-9, PMID: - DOI - PMC - PubMed
    1. Borg R., Farrugia Wismayer M., Bonavia K., Farrugia Wismayer A., Vella M., van Vugt J. J. F. A., et al. . (2021). Genetic analysis of als cases in the isolated island population of Malta. Eur. J. Hum. Genet. 29, 604–614. doi: 10.1038/s41431-020-00767-9, PMID: - DOI - PMC - PubMed
    1. Brenner D., Yilmaz R., Müller K., Grehl T., Petri S., Meyer T., et al. . (2018). Hot-spot kif5a mutations cause familial als. Brain 141, 688–697. doi: 10.1093/brain/awx370, PMID: - DOI - PMC - PubMed
    1. Brooks B. R., Miller R. G., Swash M., Munsat T. L., World Federation of Neurology Research Group on Motor Neuron Diseases (2000). El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 1, 293–299. doi: 10.1080/146608200300079536, PMID: - DOI - PubMed

LinkOut - more resources