Exome-wide rare variant analysis in familial essential tremor

Díez-Fairén, Mónica; Houle, Gabrielle; Ortega‐Cubero, Sara; Bandrés‐Ciga, Sara; Álvarez, Ignacio; Cárcel, María; Ibáñez, Laura; Fernández, María Victoria; Budde, John; Trotta, Jean-Rémi; Tonda, Raúl; Chong, Jessica X.; Bamshad, Michael J.; Nickerson, Deborah A.; Aguilar, Miquel; Tartari, Juan Pablo; Gironell, Alexandre; García‐Martín, Elena; Agúndez, José A.G.; Alonso‐Navarro, Hortensia; Jiménez‐Jiménez, Félix Javier; Fernández, Manel; Valldeoriola, Francesc; Martı́, Marı́a José; Tolosa, Eduard; Coria, F; Pastor, María A.; Vilariño‐Güell, Carles; Rajput, Alex; Cruchaga, Carlos; Rouleau, Guy A.; Pástor, Pau

doi:10.1016/j.parkreldis.2020.11.021

Cited by 12 publications

(5 citation statements)

References 39 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, a recent whole-exome sequencing of eight autosomal-dominant ET families of Spanish origin revealed the absence of rare functional variants co-segregating with ET in more than two families. 23 Specifically, the study identified 15 ET-segregating rare variants with 13 of them family-specific, which indicates significant genetic heterogeneity of ET even within the same ethnic group.…”

Section: Discussionmentioning

confidence: 95%

Whole-Genome Study of a Multigenerational Family with Essential Tremor

Zhang

Rohani

Haghighi

et al. 2021

Can. J. Neurol. Sci.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 95%

Whole-Genome Study of a Multigenerational Family with Essential Tremor

Zhang

Rohani

Haghighi

et al. 2021

Can. J. Neurol. Sci.

View full text Add to dashboard Cite

show abstract

“…Indeed, family history, is not even included in the diagnostic criteria for ET by the Consensus Statement on the Classification of Tremors [50]. Gene variants which segregate with ET in kindred studies may often not be significantly associated with ET in larger case-control analyses [116]. Establishing a genetic link between ET and PD consequently remains challenging despite these reported kindreds.…”

Section: Essential Tremormentioning

confidence: 99%

Parkinsonism and tremor syndromes

Bellows

Jankovic

2022

Journal of the Neurological Sciences

View full text Add to dashboard Cite

“…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][5][6][7][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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

View full text Add to dashboard Cite

Background: Essential tremor (ET) is a highly prevalent neurological disease that frequently runs in families. A recent and controversial proposal is to separate ET patients into two distinct groups – ET vs. ET-plus. If this were a valid construct, one would expect in familial aggregation studies to observe that ET-plus would cluster in some families yet be absent in others, rather than being randomly distributed across families. We examined whether there is evidence of familial aggregation of ET-plus. Methods: Probands (n=84 [56 ET-plus and 28 ET]) and their first- and second-degree relatives (n=182 and 48) enrolled in a genetics study. Chi-squares and generalized estimating equations (GEE) tested associations between probands’ ET-plus status and the ET-plus status of their relatives. Results: Chi-squares analyses revealed that ET-plus was no more prevalent in relatives of probands diagnosed with ET-plus than in relatives of probands diagnosed with ET, p>0.05. Restricting relatives to first-degree relatives similarly did not detect a significant association (p = 0.88). GEE yielded similar results (respective p’s = 0.39 and 0.81). Conclusion: The data demonstrate that ET-plus does not seem to aggregate in families. As such, they do not lend support to the notion that ET-plus is a valid biological construct.

show abstract

Exome-wide rare variant analysis in familial essential tremor

Cited by 12 publications

References 39 publications

Whole-Genome Study of a Multigenerational Family with Essential Tremor

Whole-Genome Study of a Multigenerational Family with Essential Tremor

Parkinsonism and tremor syndromes

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

Contact Info

Product

Resources

About