Exome sequencing is a valuable approach in critically ill patients with suspected monogenic disease: Diagnosis of X-linked centronuclear myopathy in preterm twins

Johannsen, Jessika; Hempel, Maja; Diehl, Thilo; Haack, Tobias B.; Denecke, Jonas

doi:10.1016/j.pedneo.2016.05.007

Cited by 2 publications

(1 citation statement)

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“…Causative MTM1 variants identified in XLMTM cases are typically detected by exomic sequencing approaches; next-generation sequencing of the exome or candidate panel of genes, or Sanger sequencing of MTM1 exons [1,3,4]. While these approaches cover intronic sequences directly flanking each exon, they fail to detect deep intronic variants.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.

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Section: Introductionmentioning

confidence: 99%