Identifying Susceptibility Loci for Tourette’s Syndrome in a Densely Affected Pedigree

Need/Problem: Tourette’s Syndrome is a highly genetic condition with no effective treatment. We need to identify the genetic causes of this disorder in order to develop treatments.

Grant Summary: This grant will take advantage of an extraordinary family from England that is both large and enriched for Tourette’s Syndrome in order to identify genes associated with Tourette’s Syndrome.

Goals and Projected Outcomes: The goal of our study is to identify a gene or genes with altered function in this family, that predisposes individuals to develop Tourette’s Syndrome.

James J. Crowley, PhD

Grant Details: Tourette’s Syndrome (TS) is a poorly-understood neuropsychiatric illness characterized by recurrent, non-rhythmic tics. Diagnostic criteria for TS require age of onset <18 years, multiple motor and at least one vocal tic occurring for >1 year. Most children with TS experience a nearly irresistible somatosensory urge that precedes tics, which is momentarily relieved by the completion of a tic. The lifetime prevalence of TS is ~1% worldwide and males are affected ~4x more than females. TS is often comorbid with OCD and ADHD, leading to a constellation of neurological and psychiatric symptoms that cause profound personal and societal costs. TS is highly genetic and first-degree relatives of TS cases have a 10-30 fold increased risk of TS compared with the general population, representing one of the highest recurrence risks in psychiatry.

Little is known for certain about what causes TS, and existing treatments are far from optimal. Currently there are only two FDA approved medications to treat TS (haloperidol and pimozide), and each is associated with frequent intolerable side effects. Therefore, it is essential that we identify new effective and safe treatments. Genetics is a promising route to nominate potential new treatment mechanisms.
Unfortunately, the identification of TS susceptibility genes has been challenging. Over a dozen simple linkage analyses and >50 candidate-gene studies have produced inconsistent results. Critically important for this study, however, there is evidence from large pedigrees for a few rare, highly penetrant mutations (i.e., HDC, SLITRK1, CNTNAP2). Each of these genes has provided novel insight into disease pathophysiology and the HDC (histidine decarboxylase) finding has even motivated a new clinical trial, with promising initial results. Therefore, we propose here to examine the largest known TS pedigree on a genomic level.

With the advent of high-throughput technologies, we can now search densely affected pedigrees for specific variants that may contribute to risk for TS. We have access to DNA from a remarkable six-generation British pedigree with an exceptional prevalence of TS and two co-heritable conditions: chronic mild tics (CMT) and obsessive-compulsive disorder (OCD). This 122-member pedigree contains 35 cases with TS, 12 with CMT and 7 with OCD (DNA is available for 57 individuals: 25 TS, 9 CMT, 6 OCD, 17 unaffected). The lifetime prevalence of TS and related disorders in this large pedigree makes it a strong candidate for identifying genetic risk factors of near-Mendelian effects. Our search strategy will be iterative and involve a combination of methodologies. First, we will use existing genome-wide linkage data and a case-only approach to identify genomic regions sharing identity-by-descent. Second, we will genotype all 57 available DNA samples with a microarray providing information for 2.5 million single nucleotide polymorphisms (SNPs) to identify shared segments and runs of identity-by-state. Third, a subset of the 20 most informative samples will then be whole genome sequenced to identify putative causative mutations. Fourth, and finally, all 57 samples will be genotyped for putative causal mutations to examine patterns of inheritance. Successful completion of this study has great potential to identify novel, highly penetrant mutations causing TS and related conditions, opening up a window into their pathophysiology.

2019-04-16T13:55:57-04:00