Challenges in essential tremor genetics

Abstract

The field of essential tremor (ET) genetics remains extremely challenging. The relative lack of progress in understanding the genetic etiology of ET, however, does not reflect the lack of a genetic contribution, but rather, the presence of substantial phenotypic and genotypic heterogeneity. A meticulous approach to phenotyping is important for genetic research in ET. The only tool for phenotyping is the clinical history and examination. There is currently no ET-specific serum or imaging biomarker or defining neuropathological feature (e.g., a protein aggregate specific to ET) that can be used for phenotyping, and there is considerable clinical overlap with other disorders such as Parkinson's disease (PD) and dystonia. These issues greatly complicate phenotyping; thus, in some studies, as many as 30-50% of cases labeled as "ET" have later been found to carry other diagnoses (e.g., dystonia, PD) rather than ET. A cursory approach to phenotyping (e.g., merely defining ET as an "action tremor") is likely a major issue in some family studies of ET, and this as well as lack of standardized phenotyping across studies and patient centers is likely to be a major contributor to the relative lack of success of genome wide association studies (GWAS). To dissect the genetic architecture of ET, whole genome sequencing (WGS) in carefully characterized and well-phenotyped discovery and replication datasets of large case-control and familial cohorts will likely be of value. This will allow specific hypotheses about the mode of inheritance and genetic architecture to be tested. There are a number of approaches that still remain unexplored in ET genetics, including the contribution of copy number variants (CNVs), 'uncommon' moderate effect alleles, 'rare' variant large effect alleles (including Mendelian and complex/polygenic modes of inheritance), de novo and gonadal mosaicism, epigenetic changes and non-coding variation. Using these approaches is likely to yield new ET genes.

Keywords: Complex Disease; Essential Tremor; Genetics; Génétique; Mendelian; Tremblement essentiel.