Objective:

Background:

ERBB4 variants were reported to cause amyotrophic lateral sclerosis (ALS). However, gene burden analyses revealed that rare variants in ERBB4 were not enriched in ALS cases. These results leave the pathogenic role of ERBB4 in ALS unclear.

Design/Methods:

A total of 250 ALS patients, 714 unrelated patients, and 8665 healthy controls were included in this study. The non-ALS patients include spinocerebellar ataxia (n=119), hereditary spastic paraplegia (n=89), neuromuscular disease (n=80), leukoencephalopathy (n=75), cognitive disorders (n=73), Charcot-Marie-Tooth (n= 2), Parkinson's disease (n=35) and dystonia (n=28), paroxysmal kinesigenic dyskinesia (n=12), mitochondrial disease (n=12) and other neurological diseases (n=119). Next-generation sequencing was performed. ERBB4 encoding non-synonymous variants with low frequency and predicting damage were filtered. The allele frequencies of low-frequency and deleterious ERBB4 variants were compared.

Results:

A total of 20 variants in ERBB4 were identified in 35 patients with ALS or non-ALS. Three ERBB4 deleterious variants were identified in five sporadic ALS patients, 11 non-ALS patients, and 28 controls. There was no significant difference in allele frequencies between the ALS and non-ALS groups. In addition, four reported pathogenic variants (c.158A>G, c.284G>A, c.965T>A, and c.1624G>A) were identified in patients with neuromuscular disease or leukoencephalopathy as well as normal controls. Taking the evidence from this study into account, c.158A>G was classified as an uncertain significance variant and c.284G>A was classified as likely benign, while the others were classified as uncertain significance.

Conclusions: