We report a novel intronic variant in the MTM1 gene in 4 males in a family with severe X-linked myotubular myopathy. The AG variant in deep intronic space activates a cryptic 5′ donor splice site resulting in the inclusion of a 48-bp 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-mediated decay. We conclude that affected males produce no, or low, levels of MTM1 mRNA likely leading to a significant reduction of myotubularin-1 protein resulting in the severe neonatal myopathy present in this family. The study highlights the need to consider noncoding variants in genomic screening in families with X-linked myotubular myopathy.
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