Figure 3.

Missense pathogenic variants in the MUSK gene are most severe in the Ig1 domain and most frequently found in the kinase domain

Pathogenic variants that have been observed in patients to date are plotted along their position within the MuSK protein and separated by CMS (on the left) and FADS (on the right). Variant color is given based the disease severity scale from fetal (purple) to adulthood (cyan) onset of symptoms. Null alleles consistently resulted in the most severe phenotype. For missense variants, those that impact the extracellular domain (Ig1 or Frz-like) were associated with earlier onset of symptoms. Variants were most frequent in the kinase domain (which is also the largest domain). The kinase domain variants had the largest range of disease onset. Variants that were observed in patients who trialed and discontinued pyridostigmine are marked with an asterisk (∗); all patients with extracellular missense variants discontinued pyridostigmine, but so did many patients with kinase variants. The most frequent combination of variants in compound heterozygotes involves one null allele and one missense allele.