Journal article

Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy

Samantha J Bryen, Emily C Oates, Frances J Evesson, Jessica K Lu, Leigh B Waddell, Himanshu Joshi, Monique M Ryan, Beryl B Cummings, Catriona A McLean, Daniel G MacArthur, Andrew J Kornberg, Sandra T Cooper

European Journal of Human Genetics | Springer Nature | Published : 2021


X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G..

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Awarded by National Health and Medical Research Council of Australia

Awarded by National Heart, Lung and Blood Institute

Funding Acknowledgements

This study was supported by the National Health and Medical Research Council of Australia (APP1048816 and APP1136197 STC, APP1080587 STC, DGM, GNT1090428 ECO). SJB is supported by a Muscular Dystrophy New South Wales PhD scholarship. WES, WGS and RNA-seq was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 to DGM and Heidi Rehm. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.