Novel compound missense variants in MUSK impair LRP4-MUSK-DOK7 complex associated with congenital myasthenic syndrome 9 and insights into genotype-phenotype correlation

Abstract Background:Congenital myasthenic syndromes are a group of rare neuromuscular transmission disorders. The muscle-specific kinase gene MUSK is one of the disease-causing genes.Method:Trio whole exome sequencing was performed in a patient family with congenital laryngeal achondroplasia. In vitro experiments in HEK293T cells were performed to evaluate the mutant proteins' subcellular distribution and the interactions with LRP4 and DOK7. Furthermore, we reviewed the genotype-phenotype correlations of MUSK variants from the reported literature and our patient.Result:Two novel missense variants, c.1043A>C(p.Gln348Pro) and c.2360C>T(p.Ala787Val) of MUSK, were detected in an 11-month-old girl. The variants were inherited from maternal and paternal, respectively. Compared with the wild-type MUSK protein, the two variants overexpressed in HEK293T cells localized in cytoplasmic rather than the cell membrane. The Gln348Pro was detected to impair the interaction with LRP4 and DOK7 partly. The Ala787Val variant was detected to impair the interaction with DOK7 completely. The genotype-phenotype analysis demonstrated that patients with biallelic truncation variants had earlier onset age than those with biallelic missense variants or missense variants with truncation variants. While considering biallelic missense variants, we found that the patients with variants localized in the tyrosine kinase domain had earlier onset age than those carrying variants in the Ig-like domain and had a higher mortality rate.Conclusion:In this study, we identified two novel MUSK variants cause severe fatal CMSs, expanding the spectrum of MUSK variants. In addition, our data suggest that the null variants or missense variants localized in tyrosine kinase might lead to more severe outcomes, which could give some reminders in prognostication.