SMRT Grant Winner: Hunting for Answers in Spinocerebellar Ataxia

A hearty congratulations to Cleo van Diemen at the University Medical Center Groningen for winning the 2019 Neuroscience SMRT Grant!
Van Diemen’s impressive proposal involves using PacBio long-read sequencing to find new genetic mechanisms associated with spinocerebellar ataxia (SCA). While some 70% of SCA patients can get clear diagnostic and prognostic information because they have one of the ~37 genes known to be associated with this condition, 30% of patients have no such clarity. In this project, van Diemen and her colleagues will use their SMRT Grant award to generate highly accurate long reads for two SCA patients with unknown disease etiology.
As team-leader of the research & development unit of the genome diagnostics section of the genetics department, van Diemen aims to introduce new technologies to help her colleagues achieve their research and diagnostic goals. In this case, she is working with a scientist focused on SCA patients to find a way to diagnose previously unsolvable cases.
So far, existing approaches have included standard linkage analysis, SNP arrays to look for some known structural variants, exome sequencing, and gene expression analysis. Now, van Diemen hopes that adding structural variant detection with SMRT Sequencing will provide some new answers. Repeat expansions are among the possible culprits. “Repeat genes have been identified in a lot of ataxias,” van Diemen says. With SMRT Sequencing, it will finally be possible “to do this genome-wide approach for new repeat genes.”
Structural variation is another potential source of causal mechanisms for the unexplained SCA cases. “There is some evidence that structural variants may play a role in ataxias,” van Diemen says. But SNP arrays lack the ability to discover new variants or to detect complex situations, such as inversions. And short-read sequencing often misses these large elements. “With long-read sequencing, it’s easier to identify them,” she adds.

Ultimately, the goal is to give all SCA patients the DNA-based information that will help them manage their condition. “There are some differences in the phenotypic spectrum, so knowing the genetic basis can help patients understand what they will face in the future and also makes it possible to consider genetic testing for family counseling,” van Diemen says. “That’s the clinical importance of having a genetic diagnosis.”
This SMRT Grant represents van Diemen and her team’s first use of PacBio sequencing. She believes it will be “a good starting point” that will help them understand how to apply long-read sequencing for larger-scale studies in the future. “We are looking forward to it,” she says. “It’s a great opportunity.”
 
We’re excited to support this research and look forward to seeing the results. Thank you to our co-sponsor and Certified Service Provider, the Center for Genomic Research at the University of Liverpool, for supporting the 2019 Neuroscience SMRT Grant Program.
Learn more about upcoming SMRT Grant Programs for a chance to win free sequencing.