Whole-Genome Study of a Multigenerational Family with Essential Tremor

Abstract

Background: Essential tremor (ET) is a common movement disorder with ˜5% prevalence in individuals above the age of 65, but in rare cases, it arises during childhood. Growing evidence suggests the role of cerebellum in the disease mechanism. ET is highly heritable, however, poor replication of risk loci point to its significant heterogeneity. Thus, it is important to genetically investigate kindreds with a strong aggregation of ET. Methods: We conducted a clinical and whole-genome investigation of a large Caucasian Canadian family, in which six out of eight patients are affected by childhood-onset ET in four consecutive generations. Eight family members were available for study, including three patients affected by ET. Whole-genome sequencing (WGS) was conducted for the four most informative individuals, followed by Sanger sequencing in the entire kindred. Results: We searched for rare variants absent in the eldest unaffected individual, but present in the patients (two siblings and their third-degree relative). Our stringent whole-genome filtering approach revealed a rare heterozygous p. Arg90Gln substitution in TCP10L (rs151233771) in all three investigated patients. Sanger sequencing confirmed the p. Arg90Gln variant and revealed its absence in the rest of the family members. Conclusions: Whole-genome data of the family with ET resulted in a single candidate gene mapped to 21q22.11 locus (TCP10L) with the highest brain expression in cerebellum. Our study encourages future replication studies to validate the genetic link between TCP10L and ET, and suggests the p. Arg90Gln variant for functional investigation.

Lack of Familial Aggregation of the “Essential Tremor-Plus” Phenotype in Familial Essential Tremor

“…Its hallmark clinical feature is kinetic tremor, although additional motor and non-motor features may occur [2, 3]. ET clusters or aggregates within families [4-8] and greater proportions of ET probands have relatives diagnosed with ET than do non-ET probands [9]. In one analysis, first-degree relatives of ET probands were approximately five times more likely to be diagnosed with ET than were first-degree relatives of control probands [10].…”