Case reportX-linked myotubular myopathy due to a complex rearrangement involving a duplication of MTM1 exon 10
Introduction
X-linked centronuclear (“myotubular”) myopathy (XLMTM) is a predominantly severe congenital myopathy in males characterized by numerous central nuclei on muscle biopsy (for review, [1]). XLMTM is due to hemizygous mutations in the MTM1 gene on chromosome Xq28 [2] encoding myotubularin, a dual-specificity 3-phosphoinositide phosphatase with an important role in the regulation of signalling pathways involved in growth and differentiation. Dominant mutations in the dynamin 2 (DNM2) gene [3] as well as recessive mutations in the amphiphysin 2 (BIN1) [4] and skeletal muscle ryanodine receptor (RYR1) gene [5], respectively, have been implicated in autosomal forms of centronuclear myopathy (CNM), in the majority of patients associated with milder clinical features and easily distinguishable from XLMTM. However, there is clear overlap with some patients harbouring MTM1 mutations, especially those at the milder end of the clinical spectrum.
Molecular genetic analysis of the MTM1 gene is now widely available as a routine diagnostic service and disease-causing mutations have been identified in more than 400 patients [2], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Maternal carrier state is confirmed in around 85% of affected families [8], [14] and germ cell mosaicism has been reported in several instances [8], [15], [16]. Causative MTM1 mutations include deletions/insertions, nonsense, missense and splice mutations, with approximately equal distribution of the specific mutation classes [8], [14]. Although three substitutions account for 15% of all MTM1 mutations [7], most MTM1 mutations are private or have been reported in few families only. MTM1 mutations localize most frequently (in descending order) to exons 12, 4, 11, 8 and 9 [8], [9], [10], [14], [17], [18], [19], [20], [21] but there are no clear mutational hotspots.
Although routine MTM1 molecular analysis, typically involving sequencing of all exons with inclusion of exon–intron boundaries, will detect the majority of causative MTM1 mutations, more complex rearrangements such as duplications will remain undetected applying this approach [22]. Here we report a patient with typical clinical and histopathologic features of XLMTM due to a complex rearrangement involving a duplication of MTM1.
Section snippets
Case report
This premature male infant (35 + 1 weeks gestation) presented shortly after birth with severe hypotonia and respiratory insufficiency. In the family history he was the only affected member of a healthy non-consanguineous Caucasian couple who also had two healthy daughters and one healthy son. Three years later another healthy daughter was born. There was no family history of neuromuscular or neurological disorders; his mother had eight brothers who were all healthy. On examination he was
Molecular genetic studies
A DNA sample from the patient was received and screened for mutations in the MTM1 and, subsequently, BIN1, DNM2 and RYR1 genes by routine DNA sequencing, all of which were negative. Haplotype analysis of the patient and his healthy brother showed different haplotypes around the MTM1 gene. Because of clinical and pathological features highly suggestive of XLMTM, MLPA analysis of the MTM1 and MTMR1 genes was then performed (SALSA MLPA kit P309-A1 MTM1, MRC, Holland) revealing a duplication of MTM1
Discussion
Here we reported a male infant with characteristic clinical and histopathologic findings of X-linked myotubular myopathy (XLMTM) in the context of a complex genetic background involving duplication of exon 10 of the myotubularin (MTM1) gene.
Currently no specific mechanism is hypothesised for the complex rearrangement identified in this family. Non-allelic homologous recombination (NAHR) between low copy repeats (LCRs) is proposed to be a frequent mechanism for recurrent rearrangements and
Acknowledgements
Part of this work was supported by a grant from the Guy’s and St. Thomas’ Charitable Foundation to H.J. (Grant No. 070404). The support of the National Commissioning Group (NCG) of the United Kingdom to the Dubowitz Neuromuscular Centre and Guy’s Hospital is gratefully acknowledged. F.M. is supported by the Great Ormond Street Children’s Hospital Charity.
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Approach to the diagnosis of congenital myopathies
2014, Neuromuscular DisordersCitation Excerpt :Rare mutations are intronic and are not identified on sequencing of the coding exons and flanking regions. Complex genomic rearrangements associated with XLMTM have also been reported recently [55,56]. Analysis of cDNA generated from muscle biopsy is recommended for patients with the typical phenotype to fully exclude MTM1 if a mutation is not identified on genomic DNA [57].
198th ENMC International Workshop: 7th Workshop on Centronuclear (Myotubular) myopathies, 31st May - 2nd June 2013, Naarden, The Netherlands
2013, Neuromuscular DisordersCitation Excerpt :Private mutations account for 80% of the 298 known mutations. Mutations have been reported in all exons of the gene and include missense, nonsense, and splice-site mutations, initiation defects, small insertions, deletions and insertion–deletions [6] as well as more recently reported large deletions and duplications [35,38,39]. The majority of mutations are clustered in 5 out of the 15 exons and 8 mutations are found in ∼25% of families.
Large duplication in MTM1 associated with myotubular myopathy
2013, Neuromuscular DisordersCitation Excerpt :While MTM1 mutations have been identified in the vast majority of patients with a consistent clinical and histopathologic history, 10% of males with a suspected diagnosis of myotubular myopathy remain genetically unresolved [23], suggesting either additional genetic causes for myotubular myopathy or that MTM1 mutations in some individuals are not recognized by conventional diagnostic techniques. A recent case report by Trump and colleagues [9], described a patient with a severe presentation of CNM. Routine sequencing did not identify a pathogenic mutation in MTM1.
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- 1
Current address: Regional Molecular Genetics Laboratory, Great Ormond Street Hospital, London, UK.
- 2
These authors equally contributed to this work.