Abstracts

Rationale: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by benign tumor growth in all major organs and is the leading genetic cause of both epilepsy and autism. The TSC Alliance founded a Natural History Database (NHD) in 2006 that has grown as a research resource, with 13 publications using the data to date. Genetic results are the most requested data from the NHD. Upon analysis of the NHD for quality improvement, we discovered that only 59% of enrolled participants had a record of genetic testing. This data gap led us to develop the Whole Genome Sequencing (WGS) pilot study. This initiative allowed us to start completing the NHD entries while simultaneously expanding the genetic dataset for use by TSC researchers.

Methods: We submitted 20 patient DNA samples extracted from white blood cell pellets to the Translational Genomics Research Institute (TGen) for WGS. Through this initiative, we were able to clinically validate results at GeneDx and return these results along with a virtual genetic counseling session through our collaborators at the University of Texas Health Science Center session free of charge to participants who opted in.

Results: WGS yielded a very clear genetic finding in either the TSC1 or TSC2 gene in 13 of 20 participants (i.e., variants previously found in other individuals with TSC and known to cause disease). In 6 of the 20 participants, WGS revealed novel variants, which are very likely causative due to the nature of the variant including a large inversion that would not have been captured via traditional sequencing methods. A single sample had no clear variant in TSC1 or TSC2, consistent with the 10% of clinically diagnosed individuals with no identifiable genetic etiology. This remains a significant finding as it begs further research into what led to a TSC diagnosis in the participant without a clear genetic result. Under current IRB protocols, we were unable to provide the negative research result back to the single participant. Out of the 20 samples, we provided CLIA-certified results with genetic counseling sessions to 9 families (45%) and have interest from an additional family. We did not hear back from 9 individuals, 2 of whom were siblings.

Conclusions: WGS can provide insights into disease-causing DNA variants, even for diseases in which the genetic etiologies are well studied. WGS offers a unique opportunity to obtain sequencing results, including variants that would not be recognized with traditional targeted sequencing, while also providing a large dataset for research exploration. This study has now led to a larger WGS project with a goal of sequencing 500 individuals with TSC and funding seed grants for use of this dataset once completed. Our vision is that by centrally providing this data researchers will be able to explore potential disease modifiers outside of the TSC1/2 genes and hopefully extrapolate additional genotype-phenotype correlations with the ultimate goal of enabling personalized medicine in the future.

Funding: Funding for this project was a generous donation from Julian Gangolli.