Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy

Data de publicació: 01/03/2016

Autors de IIS La Fe

• Vincenzo Lupo

  Autor

• Francisco Garcia Garcia

  Autor

• Paula Sancho Salmeron

  Autor

• Rafael Sivera Mascaró

  Autor

• Joaquin Dopazo Blazquez

  Autor

• Celedonio Marquez Infante

  Autor

• Carlos Casasnovas Pons

  Autor

• 

  Teresa Sevilla Mantecón

  Autor

• Carmen Espinos Armero

  Autor

Autors aliens a IIS La Fe

• Tello C
• García-Romero M
• Villarreal L
• Alberti A
• Pascual-Pascual SI

Grups d'Investigació

• Patología Neuromuscular y Ataxias

  

  Investigador Principal

  Teresa Sevilla Mantecón

Abstract

Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNA382 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJ82 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.