Evaluating Familial Essential Tremor with Novel Genetic Approaches: Is it a Genotyping or Phenotyping Issue?

  • Pedro Gonzalez-Alegre
  • Jorge Di Paola
  • Kai Wang
  • Shay Fabbro
  • Hung-Chun Yu
  • Tamim H. Shaikh
  • Benjamin W. Darbro
  • Alexander G. Bassuk

Abstract

Background: Essential tremor is a common movement disorder with a strong heritable component. Large families with inherited forms of essential tremor have undergone genetic analyses by different approaches. However, our knowledge of genetic variants unequivocally linked to essential tremor is remarkably limited. Several explanations have been put forth to explain this challenge, including the possibility of mutations in non-coding areas of the genome.

Methods: We encountered a family with highly penetrant, autosomal dominant tremor. We hypothesized that, if a single coding gene mutation was responsible for the phenotype, novel genetic tools would allow us to identify it. We employed single nucleotide polymorphism (SNP) arrays in 17 members of this family followed by next generation whole-exome sequencing in five affected subjects.

Results: We did not identify any copy number variant or mutation that segregated with the disease phenotype.

Discussion: This study emphasizes the remarkably challenging field of tremor genetics and indicates that future studies should perhaps shift to analysis of the non-coding genome.