The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt

Biallelic loss of function variants in the MUSK gene result in two allelic disorders: 1) congenital myasthenic syndrome (CMS; OMIM 616325), a neuromuscular disorder which has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness and 2) fetal akinesia deformation sequence (FADS; OMIM 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene ,including: 1)a deletion of exons 2-3, leading to an in-frame MuSK protein lacking the Ig1 domain and 2) a deletion of exons 7-11 leading to an out-of-frame truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.