Weak association of pathogenic ERBB4 variants with amyotrophic lateral sclerosis

Introduction ERBB4 variants were reported to cause amyotrophic lateral sclerosis (ALS). However, gene burden analyses did not find an enrichment of rare variants in patients, leaving the pathogenic role of ERBB4 in ALS unclear. Therefore, this study aimed to reassess the association of ERBB4 variants with ALS.Methods Next-generation sequencing was performed in 250 ALS and 714 non-ALS patients. Low-frequency, deleterious non-synonymous ERBB4 variants were filtered, and their allele frequencies were compared between groups.Results In total, 42 low-frequency and deleterious ERBB4 variants were identified in patients and normal controls, with three variants in all groups. There was no significant difference in allele frequencies between ALS and non-ALS groups. Additionally, four reported pathogenic variants (c.158A > G, c.284G > A, c.965T > A, and c.1624G > A) were observed in patients with neuromuscular disease or leukoencephalopathy, as well as normal controls. Based on the evidence from this study, c.284G > A was reclassified as a likely benign variant, while the others were reclassified as uncertain significance according to the American College of Medical Genetics and Genomics Guidelines.Discussion These results suggest a modest association between ERBB4 variants and ALS, underscoring the need for clinicians to conduct more careful molecular diagnosis and genetic consultations for ALS patients with ERBB4 variants.