Twenty years of molecular analyses in amyotrophic lateral sclerosis: Genetic landscape of Italian patients

Merit Lamp, Paola Origone, Alessandro Geroldi, Simonetta Verdiani, Fabio Gotta, Claudia Caponnetto, Grazia Devigili, Lorenzo Verriello, Carlo Scialò, Corrado Cabona, Antonio Canosa, Irene Vanni, Emilia Bellone, Roberto Eleopra, Paola Mandich

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous genetic background. Because mutation analysis by Sanger sequencing is costly and time-consuming, in recent years, next-generation sequencing (NGS) techniques have become of much interest. This study analyses the results of 20 years of molecular analyses in ALS patients in our laboratory using traditional methods and NGS. Almost 300 ALS patients underwent genetic analysis with Sanger sequencing of 7 genes or with an NGS panel of 23 genes. The C9orf72 expansion was tested by fragment size analysis. Sanger sequencing revealed mutations in 23.8% of familial and 3.8% of sporadic cases, whereas NGS detected potentially pathogenic variants in 45.5% of familial and 5.4% of sporadic cases and variants of unknown significance in 30.3% of patients. In 11.8% of patients, potentially causative mutations were found in 2 or more ALS genes. Compared to traditional methods, NGS is more effective in revealing possibly causal variants, but counseling patients becomes more complicated due to frequent variants of unknown significance and potentially oligogenic cases.

Original languageEnglish
JournalNeurobiology of Aging
DOIs
Publication statusAccepted/In press - Jan 1 2018

Keywords

  • Amyotrophic lateral sclerosis
  • Genetic analysis
  • Mutation
  • Next-generation sequencing
  • Sanger sequencing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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