Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy

Teresa Esposito, Simone Sampaolo, Giuseppe Limongelli, Antonio Varone, Daniela Formicola, Daria Diodato, Olimpia Farina, Filomena Napolitano, Giuseppe Pacileo, Fernando Gianfrancesco, Giuseppe Di Iorio

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Abstract

Background: We report an Italian family in which the proband showed a severe phenotype characterized by the association of congenital fiber type disproportion (CFTD) with a left ventricular non-compaction cardiomyopathy (LVNC). This study was focused on the identification of the responsible gene/s. Methods and results. Using the whole-exome sequencing approach, we identified the proband homozygous missense mutations in two genes, the myosin heavy chain 7B (MYH7B) and the integrin alpha 7 (ITGA7). Both genes are expressed in heart and muscle tissues, and both mutations were predicted to be deleterious and were not found in the healthy population.The R890C mutation in the MYH7B gene segregated with the LVNC phenotype in the examined family. It was also found in one unrelated patient affected by LVNC, confirming a causative role in cardiomyopathy.The E882K mutation in the ITGA7 gene, a key component of the basal lamina of muscle fibers, was found only in the proband, suggesting a role in CFTD. Conclusions: This study identifies two novel disease genes. Mutation in MYH7B causes a classical LVNC phenotype, whereas mutation in ITGA7 causes CFTD. Both phenotypes represent alterations of skeletal and cardiac muscle maturation and are usually not severe. The severe phenotype of the proband is most likely due to a synergic effect of these two mutations.This study provides new insights into the genetics underlying Mendelian traits and demonstrates a role for digenic inheritance in complex phenotypes.

Original languageEnglish
Article number91
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

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Keywords

  • Congenital type fiber disproportion
  • Integrin alpha 7 (ITGA7)
  • Left ventricular noncompact cardiomyopathy
  • Myosin heavy chain 7B (MYH7B)
  • Whole exome sequencing

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Esposito, T., Sampaolo, S., Limongelli, G., Varone, A., Formicola, D., Diodato, D., Farina, O., Napolitano, F., Pacileo, G., Gianfrancesco, F., & Di Iorio, G. (2013). Digenic mutational inheritance of the integrin alpha 7 and the myosin heavy chain 7B genes causes congenital myopathy with left ventricular non-compact cardiomyopathy. Orphanet Journal of Rare Diseases, 8(1), [91]. https://doi.org/10.1186/1750-1172-8-91