Tourette Syndrome Linked to De Novo Coding Variants

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The findings may help in the development of novel therapeutics for Tourette syndrome.
The findings may help in the development of novel therapeutics for Tourette syndrome.

Likely gene disrupting (LGD) de novo coding variants identified through whole-exome sequencing (WES) were found to significantly contribute to the expression of Tourette disorder (TD), according to research published recently in Neuron.1

The investigative group, composed of genetics researchers and child psychiatrists from multiple institutions in the United States and the Netherlands, conducted WES of 511 TD trios: 325 obtained from the Tourette International Collaborative Genetics cohort and 186 replication samples provided by the Tourette Syndrome Association International Consortium on Genetics. De novo damaging variants isolated in at least 400 genes were linked to TD risk in 12% of cases.

Previous research on copy number variations in TD indicated the regular occurrence of de novo enrichment in probands, particularly of missense (Mis) variants identified as damaging by PolyPhen2 (Missense 3 or Mis3; PolyPhen2 ([umDiv] score R≥0.957).2-7

In their evaluation of the Tourette International Collaborative Genetics samples, the investigators were able to confirm their hypothesis that de novo LGD variants were highly overrepresented in the Tourette's cases compared with in unaffected parent and sibling sample controls, at a rate ratio (RR) of 2.14 (95% CI, 1.28-3.61; P =.006). This finding was replicated in the Tourette Syndrome Association International Consortium on Genetics cohort, using the 1-sided rate ratio test, (RR, 1.97; 95% CI, 1.03-3.68; P =.04). The overall rate of mutations did not differ significantly between the 2 TD cohorts.

The combined cohorts had an RR of 2.32 for de novo variant burden in the 484 available TD trios. The researchers found a significant excess of de novo LGD variants alone (RR, 2.32; 95% CI, 1.37-3.93; P =.002, Poisson regression), and damaging LGD + Mis3 variants (RR, 1.37; 95% CI, 1.11-1.69; P =.003).

Using a maximum likelihood estimation, the investigators were further able to identify 5 recurrent genes that potentially cause the damage associated with TD. One of those, the TTN gene, failed to meet established q-thresholds (q<0.3), leaving 3 "probable" TD risk genes (the CELSR3 [Cadherin EGF LAG 7-pass G-type receptor 3], NIPBL [Nipped-B-like], and FN1 [fibronectin 1] genes) and 1 "high confidence" candidate, the WWC1 (WW and C2 domain containing 1) gene.

"The four likely TD genes span a range of biological pathways and functional ontologies and are all clearly brain expressed," the investigators wrote, and all provide "interesting avenues for additional investigations." Identifying genetic links to the unknown pathophysiology of TD provides better understanding of the etiology and helps reduce fundamental obstacles to the development of novel therapeutic agents, they suggested.

References

  1. Willsey JA, Fernandez TV, Yu D, et al. De novo coding variants are strongly associated with Tourette disorder. Neuron. 2017;94:486-499. doi: 10.1016/j.neuron.2017.04.024
  2. Fernandez TV, Sanders SJ, Yurkiewicz, IR, et al. Rare copy number variants in Tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry. 2012;71:392-402.  doi: 10.1016/j.biopsych.2011.09.034
  3. McGrath LM, Yu D, Marshall C, et al. Copy number variation in obsessive-compulsive disorder and Tourette syndrome: a cross-disorder study. J Am Acad Child Adolesc Psychiatry. 2014;53:910-919. doi: 10.1016/j.jaac.2014.04.022
  4. Nag A, Bochukova EG, Kremeyer, B, et al.; Tourette Syndrome Association International Consortium for Genetics. CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. PLoS ONE. 2017;8(3):e59061.  doi: 10.1371/journal.pone.0059061
  5. Sundaram SK, Huq AM, Wilson BJ, et al. Tourette syndrome is associated with recurrent exonic copy number variants. Neurology. 2010;74:1583-1590. doi: 10.1212/WNL.0b013e3181e0f147
  6. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–249. doi: 10.1038/nmeth0410-248
  7. Adzhubei I, Jordan DM, Sunyaev, SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7:Unit 7.20. doi: 10.1002/0471142905.hg0720s76
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