ARF1-Related Diseases in China: The Initial Study of Phenotype and Molecular Profile

The ADP-ribosylation factor 1 (ARF1) gene encodes a protein which plays a critical role in intra-Golgi transport. Clinical evidence suggests that individuals harbouring variants in the ARF1 gene display a consistent set of phenotypic features, including intellectual disability, microcephaly, epilepsy, and periventricular nodular heterotopia (PVNH).

This study describes the case of a 6-year and 5-month-old female presenting with focal seizures on a fixed side that were resistant to various anti-seizure medications. The genetic aetiology was elucidated through exome sequencing of the pedigree. The pathogenicity of the identified variant was subsequently assessed using molecular dynamics structural analysis, western blotting, and co-immunoprecipitation techniques.

A de novo variant, c.509T > C (p.Leu170Pro), was detected in the ARF1 gene, and functional analysis demonstrated that this modification is anticipated to hinder its association with the Golgi-localising, γ-adaptin ear homology domain and ARF-binding protein, thereby playing a role in the pathogenesis of the disease.

This study introduces the initial instance of ARF1-related disease in China, wherein the patient is without the presence of PVNH. The findings add novel clinical phenotypes to the range of ARF1-related diseases, and an investigation into the potential pathogenic mechanisms of this condition was conducted by confirming the deleterious impacts of the variant.