Clinical and molecular analysis of a novel variant responsive to salbutamol monotherapy during COVID-19 outbreak related to congenital and late-onset of myasthenic syndrome in large kindred

Abstract Background: Congenital myasthenic syndromes (CMSs) are a group of clinically and genetically heterogeneous disorders. Mutations in the DOK7 gene underlie CMS with fatigue and muscle weakness, which would worsen with some conventional treatments but show excellent response to special drugs. Here, we applied exome sequencing (ES) to investigate the etiology of CMS in several patients with congenital and late-onset presentations of the disease. Methods: We ascertained a big pedigree including 3 homozygous and 5 carriers, primary proband was subjected to ES, following immunological, biochemical and neurological evaluations. Molecular dynamics (MD) simulation studies were conducted to investigate the DOK7 proteins' stability. The variant’s pathogenicity was assessed using bioinformatics tools and co-segregation analysis. We adapted the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation. Results: ES results showed a novel homozygous variant (c.1139-1140delinsA:p.Ala380AspfsTer76) in the DOK7 gene. Co-segregating analysis confirmed the pathogenicity of it based on the ACMG guidelines. Interestingly, the identified variant has shown partial autosomal dominant inheritance. The MD simulation analysis revealed this variant to result in the protein function impairment. Effective treatment with salbutamol was obtained in an 18-months follow-up. Remarkably, therapeutic doses of salbutamol in severe COVID-19 patients prevented recurrence of paralysis or muscle weaknesses that occurred with a mild cold. Conclusion: We found a novel variant in the DOK7 gene, with the newly identified partial autosomal dominant inheritance. The findings were used to administer suitable drugs to the patients with maximum efficiency. Thus, ES creates a unique opportunity to promote personalized medicine.