NEW YORK (GenomeWeb) – A recent analysis of an expanded sequencing dataset underscores the role that de novo variants and structural changes play in Tourette disorder.
An international team led by investigators at the University of California, San Francisco and Purdue University performed exome sequencing on 291 affected children and their parents, adding to data for Tourette-affected parent-child trios assessed by exome sequencing in the past. Along with an overall uptick in de novo variation in affected children, the researchers found recurrent changes involving the CELSR3 gene and representatives from cell polarity pathways.
"You might expect that mutations in these cell polarity genes would affect things like neurons getting to the right place in the brain, or forming the right connections, with the appropriate directionality," co-senior author Jeremy Willsey, a psychiatry and neurodegenerative diseases researcher at UCSF, said in a statement. "Our group has already started experiments modeling the effect of mutations in these cell polarity genes during early brain development."
In particular, the de novo alterations appeared to be linked to Tourette syndrome in families with just one affected child and in Tourette cases that affected female children. The study, published online today in Cell Reports, also highlighted overlap between the de novo alterations implicated in Tourette disorder and those described in previous studies of obsessive compulsive disorder (OCD) or autism spectrum disorder (ASD).
"While tics are the defining feature of [Tourette disorder], there are many other symptoms that tend to go along with the disorder, like attention problems, learning difficulties, OCD, depression, and anxiety," co-senior author Matthew State, chair of the UCSF psychiatry department, said in a statement.
"If we knew exactly what was going wrong and could target this more specifically, not only could we do a better job of decreasing tics, but we could potentially simultaneously address multiple symptoms that accompany [Tourette disorder]," State explained, "and that in many children are more debilitating than the tics themselves."
For the new analysis, researchers from the Tourette International Collaborative Genetics Study and other consortia brought together new exome sequencing data for 873 members of 291 Tourette-affected trios — generated with Nimblegen or Agilent capture arrays and Illumina HiSeq 4000 instruments — and data for 511 affected children and their parents who were included in a study published in Neuron last spring that highlighted four potential risk genes.
The team's analyses of all 802 trios (representing more than 2,400 individuals), along with 1,184 unaffected controls and 582 sequenced trios from the Simons Simplex Collection, pointed to recurrent de novo alterations in the same four genes — WWC1, FN1, CELSR2, and NIPBL — and led to two more genes with potential ties to Tourette disorder, OPA1 and FBN2. It also confirmed another feature reported in last's year study: an overrepresentation of de novo changes in the individuals with Tourette disorder.
The researchers found that the de novo damaging variants identified in Tourette disorder were shared with OCD, even after taking into account cases in which individuals were affected by both conditions.
And along with a general uptick in potentially damaging de novo copy number changes, they reported, the Tourette cases tended to involve de novo CNVs that have also been reported in ASD trios from the Simons Simplex Collection and in conditions such as schizophrenia and epilepsy.
Some members of the same team described Tourette syndrome-associated structural variants in the NRXN1 and CNTN6 genes, identified by array-based copy number analyses, for a study published in Neuron last June.