A familial amyotrophic lateral sclerosis pedigree discordant for a novel p.Glu46Asp heterozygous OPTN variant and the p.Ala5Val heterozygous SOD1 missense mutation

J Clin Neurosci. 2020 May:75:223-225. doi: 10.1016/j.jocn.2020.03.032. Epub 2020 Mar 27.

Abstract

About 10% of Amyotrophic Lateral Sclerosis (ALS) cases are familial (FALS), mainly related to mutations in C9ORF72, SOD1, TARDBP, and FUS genes. Recent data revealed the presence of multiple variants in ALS-associated genes in FALS in excess of what is to be expected by chance. FALS patients not carrying a pathogenic genetic mutation detected in their kindred have been reported. We report a FALS case, who did not carry the p.Ala5Val heterozygous SOD1 mutation that had been detected in other affected subjects of his kindred. He underwent Next-Generation Sequencing, revealing a novel p.Glu46Asp heterozygous OPTN variant of uncertain significance (VUS). Discordant genetic test results in FALS cases within the same family and the detection of variants of uncertain significance increase the complexities of genetic counselling.

Keywords: Familial ALS; Genetic counselling; Genetic variant of uncertain significance; OPTN; SOD1.

Publication types

  • Case Reports

MeSH terms

  • Alanine / genetics
  • Amyotrophic Lateral Sclerosis / diagnosis*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Aspartic Acid / genetics
  • Cell Cycle Proteins / genetics*
  • Female
  • Genetic Testing / methods
  • Genetic Variation / genetics*
  • Glutamine / genetics
  • Heterozygote
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Mutation, Missense / genetics*
  • Pedigree
  • Superoxide Dismutase-1 / genetics*
  • Valine / genetics

Substances

  • Cell Cycle Proteins
  • Membrane Transport Proteins
  • OPTN protein, human
  • SOD1 protein, human
  • Glutamine
  • Aspartic Acid
  • Superoxide Dismutase-1
  • Valine
  • Alanine