Identification of candidate genes for familial early-onset essential tremor

Liu, Xinmin; Hernández, Nora; Kisselev, Sergey; Floratos, Aris; Sawle, Ashley; Ionita‐Laza, Iuliana; Ottman, Ruth; Louis, Elan D.; Clark, Lorraine N.

doi:10.1038/ejhg.2015.228

Cited by 37 publications

(38 citation statements)

References 69 publications

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“…For example, early onset ET cases might differ in their rates of progression and their tremor-related brain oscillatory circuits when compared to late onset ET cases [13,14]. The presence of family history in ET might indicate an underlying genetic etiology [15,16] as well as possible differences in the ability to metabolize naturally-occurring tremorgenic compounds [17]. In addition, ET cases with head tremor might have different degrees of cerebellar involvement than ET cases without head tremor, based on neuroimaging findings [18].…”

Section: Introductionmentioning

confidence: 99%

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Lee

Gan

Faust

et al. 2018

Parkinsonism & Related Disorders

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Background Essential tremor (ET) is heterogeneous in nature and cases may be subdivided based on clinical features. ET patients may thus be subdivided by age of onset, family history of tremor, and presence of head tremor. We recently described climbing fiber-Purkinje cell (CF-PC) synaptic abnormalities in ET; however, these CF pathological features have not been studied across different ET subtypes. Objectives To explore whether these CF-PC synaptic abnormalities differ across ET subtypes. Methods We studied two climbing fiber (CF-PC) synaptic pathologies (CF synaptic density and percentage of CFs in the parallel fiber [PF] territory) in the cerebella of 60 ET cases with a range of clinical presentations and 30 age-matched controls. Results Compared to controls, ET cases had lower CF synaptic density and a higher percentage of CFs in the PF territory. ET cases with tremor onset <50 years and tremor onset ≥ 50 years did not differ significantly with respect to CF synaptic density and percentage of CFs in the PF territory. Similar results were found when comparing familial vs. sporadic ET cases, and ET cases with head tremor vs. those without head tremor. Among all ET cases, lower CF synaptic density was associated with lower PC counts and higher torpedo counts. In addition, higher percentage of CFs in the PF territory was associated with lower PC counts and higher torpedo counts. Conclusions These findings support the notion that changes in the distribution of CF-PC synapses are broadly part of the neurodegenerative process in the ET cerebellum.

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Section: Introductionmentioning

confidence: 99%

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Lee

Gan

Faust

et al. 2018

Parkinsonism & Related Disorders

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“…Phenolyzer includes multiple components, including a tool to map the user-supplied phenotype to related disease, a resource that integrates existing knowledge on disease genes, an algorithm to predict previously unknown disease genes, a machine learning model that integrates multiple features to score and prioritize candidate genes and a network visualization tool to examine gene-gene and gene-disease relationships [39]. Previously, we performed WES [15] on a subset of the families (Families A, B, E and F) included in the current WGS analysis. For these families, WES did not identify the candidate genes identified in the current WGS study.…”

Section: Discussionmentioning

confidence: 99%

“…WGS which forgoes capturing is less sensitive to GC content and is more likely than WES to provide complete coverage of the entire coding region. Other factors that can affect variant and candidate gene identification include the bioinformatics pipeline (GATK version and implementation options) used and statistical analysis methods (WES study pVAAST [15, 45] versus WGS in the current study: MM-KBAC [45]).…”

Section: Discussionmentioning

confidence: 99%

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Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Odgerel

Hernández

Park

et al. 2018

Preprint

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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 variant due to incomplete coverage of the entire coding region of the genome. 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 variant classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test and prioritization of candidate genes identified within families 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>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 (family D), 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). This work has identified candidate genes and pathways for ET that can now be prioritized for functional studies.

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“…In contrast to linkage analysis WES may also be applied in smaller families with fewer generations. So far this method has been applied in several ET families [58][59][60][61]. The genes are listed in Table 1.…”

Section: Geneticsmentioning

confidence: 99%

Is essential tremor a single entity?

Hopfner

Deuschl

2017

Euro J of Neurology

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Essential tremor (ET) is a frequent movement disorder. The new tremor classification has subdivided ET into the classical form with bilateral action tremor of the hands with or without involvement of further tremor locations and without any other explaining signs or symptoms for the tremor and into 'ET plus' which comes additionally with further neurological signs of unknown origin. This will provide a better foundation for subclassifying the condition. The immediate cause of ET is a preformed oscillating network within the central nervous system as revealed with electrophysiological methods. The reason why this network is getting into the tremor mode is unclear. Pathology has so far not convincingly proved neurodegeneration for the condition but possibly adaptive changes of the brain particularly in the cerebellum are likely. Genetics have not yet provided insight into the molecular causes of the condition but several genetic diseases presenting with an ET syndrome have been uncovered. Treatment options cover medication (propranolol, primidone, topiramate) and surgical interventions with deep brain stimulation, gamma-knife surgery and the recently introduced magnetic resonance imaging guided focused ultrasound lesioning. Further progress is awaited from the better integration of large prospective cohort assessment and basic science studies on the possible etiologies. In particular, aging-related tremor may explain a large number of the patients seen in clinical practice. Currently ET is considered a clinically relatively uniform condition with presumably various underlying etiologies.

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Identification of candidate genes for familial early-onset essential tremor

Cited by 37 publications

References 69 publications

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Is essential tremor a single entity?

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