A deep intronic variant activates a pseudoexon in the MTM1 gene in a family with X-linked myotubular myopathy

We report a novel intronic variant in the MTM1 gene in four males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5 prime donor splice site resulting in the inclusion of a 48bp pseudoexon into the mature MTM1 mRNA. The variant is present in all affected males, absent in unaffected males and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediate decay. We conclude that affected males produce no, or low, levels of myotubularin-1 protein leading to a severe neonatal myopathy. The study highlights the need to consider non-coding variants in genomic screening in families with X-linked myotubular myopathy.