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Nascer e Crescer

versão impressa ISSN 0872-0754

Nascer e Crescer vol.23  supl.1 Porto mar. 2014





Discovering “X” in the myopathic equation



Jorge OliveiraI

IUnidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal. E-mail:



Congenital myopathies (CM) are a heterogeneous group of diseases, generally characterized by hypotonia and muscle weakness with onset at birth or during infancy and usually with a slowly progressive disease course. Scientific and technological developments in genomics over the last two decades have contributed to the identification of genetic causes for a significant number of myopathies. However, there are still several challenges to address both in diagnostics and in research. First, there is striking genetic and clinical heterogeneity associated to CM. In fact, although muscle biopsy is paramount for the diagnostic workup, pathognomonic findings such as cores, rods, central nuclei or fibre-type disproportion, are not gene-specific. In addition, a significant subset of these patients remains genetically unsolved, requiring further investigation that may lead to the identification of new genetic causes of CM.

Our recent research in congenital myopathies has focused on the mutational profile of the myotubularin gene (MTM1), which is defective in X-linked centronuclear myopathy (CNM). Male patients with MTM1 mutations are usually severally affected,  presenting  neonatal  hypotonia  and  inability  to maintain unassisted respiration. During the development and implementation of a mutation database for MTM1 (, we noticed that no large duplications had been reported. Large duplications in MTM1 were screened by the MLPA technique in a small group of uncharacterized CNM Portuguese patients. A large duplication spanning exons 1 to 5 was identified in a boy with a mild CNM phenotype. Further characterization revealed that this duplication causes an inframe deletion at the mRNA  level (r.343_444del). Results obtained using a low-coverage next generation sequencing (NGS) approach showed that this genomic duplication extends into the neighbouring MAMLD1 gene and subsequent analysis unveiled the presence of a MTM1/MAMLD1 fusion transcript [1]. This work demonstrates that it is clinically relevant to screen large MTM1 duplications in CNM patients since this type of mutation may account for some cases that remain genetically unanswered, as was recently validated by the publication of additional cases. It also demonstrates how different analytical approaches are often required to solve the genetic complexity of congenital myopathies; the further  application of NGS technology in these disorders shall be exemplified.



[1] Oliveira, J.; Oliveira, M.E.; Kress W.; Taipa, R.; Pires, M.M.; Hilbert, P.; Baxter, P.; Santos, M.; Buermans, H.; den Dunnen, J.T.; Santos, R. (2013). Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database. European Journal of Human Genetics. 21(5): 540-549.         [ Links ]

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