Much to researchers' chagrin, genome-wide association studies for certain complex neurodevelopmental disorders have unearthed few cogent genetic connections. Prompted by evidence supporting a genetic component for Tourette syndrome/chronic tic disorder within individual pedigrees, researchers at Wayne State University sequenced the exomes of a 10-member family with seven affected kin. In a May Annals of Neurology paper, Ahm Mahbubul Huq and his colleagues report their identification of three novel, non-synonymous single nucleotide variants — at MRPL3, DNAJC13, and OFCC1 — associated with the chronic tic phenotype in this family. Genome Technology's Tracy Vence recently spoke with Huq to find out more.
Genome Technology: Why did your group choose to pursue this sequencing study?
Ahm Mahbubul Huq: We are studying Tourette syndrome. ... Previously, I was also working on autism and ... developmental delays. For all of these disorders — which are complex traits — linkage-association studies have been disappointing. One group identifies a variant, another cannot confirm [it]. So, basically our thinking on this group of disorders was that probably the reason that these studies ... are not successful is because [the disorders] are extremely heterogeneous and each individual family probably has their own mutation, or ... there are probably very large numbers of genes that are involved. Given the heterogeneity, sequencing becomes the only reasonable approach to identify the mutation in these families.
GT: Why exome sequencing over some other approach?
AMH: Whole-genome sequencing is still very expensive. Even with exomes, the major problem is analyzing the data — to figure out which of the many, many novel variants that we identify is the culprit.
GT: How much did sequencing the exomes of the 10 family members cost?
AMH: With the 10 family members, we had to do some Sanger sequencing for verification and follow-up, and including everything, it was less than $40,000. With whole-genome [sequencing], for one sample we would probably end up spending that.
GT: What challenges specific to the phenotypic classification of neurodevelopmental disorders did your team encounter?
AMH: In Tourette, a large percentage of the individuals will also have obsessive compulsive disorder and attention deficit disorder, and our pedigree shows that. ... One issue was: Do we study Tourette syndrome as clinically defined by psychiatrists and neurologists or do we take a quantitative phenotype? Another issue was, with our family, five members ... also have anxiety and depression. ... So, how do we deal with that? Do we include anxiety and depression as a separate phenotype, or could that be alternative expression? Eventually, we decided [to take the] approach that clinicians are using: Tourette is a distinct entity. And we know from other disorders, even for simple Mendelian disorders — for example, in neurofibromatosis — expression could be very variable.
GT: Is exome sequencing headed to the clinic?
AMH: My belief is that eventually exome sequencing and microarrays [are] going to be the two tests that all clinicians will order. ... When exome sequencing is available clinically, I don't see any reason to test individual genes — which [can] sometimes cost as much as $5,000, just to test one gene — rather than sequencing [the] exome and then maybe doing a micro- array to look for deletions and duplications.
GT: When might these technologies become mainstream?
AHM: I think the technology is ready. Even now, some companies are offering exome sequencing [for] around $2,000. But ... they will only accept research samples because of liability issues. ... Within the next two years I think clinicians will be able to get this done as a clinical test.