(A) Gene structure and location of mutations in the MTM1 gene. Exons are represented as boxes. Mutation locations are indicated with mutation type coded by shape. The myotubularin protein contains 4 domains: the pleckstrin homology glucosyltransferases, Rab-like GTPase activators and myotubularins (PH-GRAM) domain, Rac1-Induced recruitment domain (RID), protein tyrosine phosphatase (PTP) and SET-interacting domain (SID). (B) X-inactivation ratios for MTM1-related myopathy manifesting and nonmanifesting carriers reported in the literature show a range of ratios without a clear pattern. (C) X-inactivation patterns are expected to follow predicted ratios if X-inactivation is the primary driver of symptom expression and severity; however, the prediction does not hold up in our cohort, suggesting the X-inactivation model of disease expression is incomplete, and additional factors exist.