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

## TL;DR

This study examines the ERBB4 gene in Chinese ALS patients and finds rare variants linked to earlier disease onset, highlighting ethnic differences in genetic risk.

## Contribution

The study identifies ERBB4 variants as potential disease modifiers in ALS and reveals ethnic differences in their prevalence.

## Key findings

- ERBB4 variants were found in 0.83% of ALS patients globally, with higher prevalence in Chinese populations.
- Carriers of ERBB4 variants had earlier disease onset compared to non-carriers.
- A splice variant reduced ERBB4 mRNA expression and was maternally inherited in a patient.

## Abstract

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.

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.

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).

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.