DOI: 10.5061/dryad.td8d20v
title: Data from: Whole genome sequencing and rare variant analysis in essential tremor families

description: Essential tremor (ET) is one of the most common movement disorders. The
 etiology of ET remains largely unexplained. Whole genome sequencing (WGS)
 is likely to be of value in understanding a large proportion of ET with
 Mendelian and complex disease inheritance patterns. In ET families with
 Mendelian inheritance patterns, WGS may lead to gene identification where
 WES analysis failed to identify the causative single nucleotide variant
 (SNV) or indel due to incomplete coverage of the entire coding region of
 the genome, in addition to accurate detection of larger structural
 variants (SVs) and copy number variants (CNVs). Alternatively, in ET
 families with complex disease inheritance patterns with gene x gene and
 gene x environment interactions enrichment of functional rare coding and
 non-coding variants may explain the heritability of ET. We performed WGS
 in eight ET families (n=40 individuals) enrolled in the Family Study of
 Essential Tremor. The analysis included filtering WGS data based on allele
 frequency in population databases, rare SNV and indel classification and
 association testing using the Mixed-Model Kernel Based Adaptive Cluster
 (MM-KBAC) test. A separate analysis of rare SV and CNVs segregating within
 ET families was also performed. Prioritization of candidate genes
 identified within families was performed using phenolyzer. WGS analysis
 identified candidate genes for ET in 5/8 (62.5%) of the families analyzed.
 WES analysis in a subset of these families in our previously published
 study failed to identify candidate genes. In one family, we identified a
 deleterious and damaging variant (c.1367G&gt;A, p.(Arg456Gln)) in the
 candidate gene, CACNA1G, which encodes the pore forming subunit of T-type
 Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and
 has been previously implicated in neuronal autorhythmicity and ET. Other
 candidate genes identified include SLIT3 which encodes an axon guidance
 molecule and in three families, phenolyzer prioritized genes that are
 associated with hereditary neuropathies (family A, KARS, family B, KIF5A
 and family F, NTRK1). Functional studies of CACNA1G and SLIT3 suggest a
 role for these genes in ET disease pathogenesis.
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