Objective: Objective: To discover novel gene variants associated with essential tremor (ET) using whole exome sequencing (WES).

Background: Background: ET, one of the most common movement disorders, affects about 5% of the population older than 65 years of age.  Although family history is common in ET, the responsible genes have largely proven elusive. Many genes, including LINGO1, SLC1A2, SCN4A, HTRA2, SORT1, FUS, TENM4, STK32B, and CTNNA3, have been implicated in ET. Polymorphisms in LINGO1 have been independently replicated in some studies (Kuhlenbäumer et al. 2014) but not in others (Müller et al. 2016).

Methods: Methods: We included families and singleton cases on our ET WES cohort. Our analyses initially focused on related subjects from 3 families, and identified shared variants, consistent with segregation. Several filters were next employed to prioritize the most likely responsible gene mutations from among all non-synonymous variants, including (1) brain expression, (2) minor allele frequency < 0.01 in public databases, and (3) predicted pathogenicity based on several algorithms.

Results: Results: Our familial ET WES cohort of 20 cases (55% female) includes 6 subjects from 3 families (2 related subjects per family), and the remaining 14 subjects are singleton cases (1 subject per family). The median age at tremor onset is 19.5 years (range 4-57 years) and the median age at enrollment was 52.5 years (range 38-75 years). All ET pedigrees show at least 2 consecutive affected generations, and have an apparent autosomal dominant inheritance pattern. Following application of filters, we identified multiple, promising shared variants within novel gene candidates for each of our 3 ET families. Additional putative damaging variants in selected genes were detected among the 14 singleton exomes, consistent with genetic replication.

Conclusions: Conclusions: WES is a promising tool for ET gene discovery. The genes and variants identified in our study are excellent candidates for further segregation analysis in ET families and for replication studies in additional ET cohorts.

References: 1. Kuhlenbäumer G et al. Genetics of essential tremor – Meta-analysis and review. Neurology 2014;82:1000-1007.

2. Muller SH et al. Genome-wide association study in essential tremor identifies three new loci. Brain 2016;139(Pt 12):3163-3169.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/whole-exome-sequencing-in-essential-tremor/