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Tourette Disorder Risk Linked to Variants in Four Genes

NEW YORK (GenomeWeb) – A team of researchers has linked variants in four genes to Tourette disorder risk.

As they reported today in Neuron, researchers led by Rutgers University's Jay Tischfield conducted whole-exome sequencing on 325 affected children and their parents to home in on four likely risk genes, including WWC1, for the disorder. Tourette disorder, a neurological condition, affects about one in a hundred people worldwide and is marked by involuntary verbal and physical tics.

The research team further estimated that some 400 genes could be implicated in Tourette risk, and said the ones they did find could point to genetic and brain pathways involved in the disorder, and to better ways to treat it.

"This research is the first of its kind establishing Tourette disorder as a genetic disease similar to other neuropsychiatric disorders like autism, where not just one gene has been identified as the cause," Tischfield said in a statement.

He and his colleagues performed whole-exome sequencing on 325 parent-child trios from the Tourette International Collaborative Genetics group to search for de novo SNVs and indels among affected children. They then replicated their findings in 186 parent-child trios from the Tourette Syndrome Association International Consortium for Genetics, and conducted Sanger sequencing-based validation for all the de novo variants uncovered in the probands.

From this, the researchers uncovered four genes that harbored multiple variants that were predicted to be gene disrupting or damaging.

They predicted one such gene — WWC1 — to be a Tourette risk gene with high confidence. WWC1, which is expressed in the brain, encodes a cytoplasmic phosphoprotein that interacts with a number of proteins and pathways. The researchers noted that it has roles in cell polarity, migration, and trafficking, as well as in learning and memory.

The other three genes — FN1, CELSR2, and NIPBL — didn't reach quite the same level of confidence as WWC1 for a role in Tourette, but the researchers still said they were likely to be involved. FN1 encodes two forms of fibronectin-1 — one that is soluble and one that is not — while CELSR2 belongs to a subfamily of non-classic cadherins.

NIPBL, however, has been previously linked to a development disorder called Cornelia de Lange syndrome. The researchers noted that they were surprised to find NIPBL variants, though the ones they linked to Tourette were located in different exons than the ones linked to Cornelia de Lange, suggesting that these variants might have less severe effects.

At the same time, the researchers determined using a maximum likelihood estimation approach that there may be as many as 400 genes that contribute to Tourette risk. Future studies involving larger cohorts would likely uncover more of these genes, they noted.

They further calculated that about 12 percent of clinical cases of Tourette likely involve de novo mutations. While such de novo mutations are rare, co-lead author and UCSF psychiatry professor Jeremy Willsey noted that he and his colleagues focused on them in their study as they tend to have more extreme effects that can help elucidate the underlying causes of a disease.

"This also translates to developing therapies: if these variants greatly increase a child's risk of Tourette disorder, we would expect that understanding these changes could potentially lead to very effective treatments for the disorder," Willsey added in a statement.