Increasing the molecular diagnostic yield in genetic diseases using spinocerebellar ataxia (SCA) as a disease model

Spinocerebellar ataxias (SCAs) are a group of genetic disorders that cause loss of balance, changes in body movements, and difficulties in speaking. For SCA patients, genetic testing is performed to find the cause of the disease. However, ~40% of the patients remain without a genetic cause. We here aim to provide genetic diagnoses for the genetically unsolved SCA patients using different strategies. First, we analyzed a cohort of unsolved patients for genetic variations in all genes known to be involved in SCA development. We found the genetic cause for 22 patients. A big challenge in diagnostics is that we also detect genetic variation without knowing the causality. This variation is of “unknown significance” for the patient. We performed different tests to reveal the significance of a number of these variants. Four variants seem disease-causing leading to a genetic diagnosis for four patients. In addition, we tested our cohort for a recently discovered disease-causing gene variation (RFC1 intronic repeat expansion) and found the genetic cause for ten patients. In another approach, we identified clinically relevant gene deletions in two unsolved cases. Finally, we identified genomic regions regulating the activity of the genes involved in the disease but did not detect any potentially disease-causing variants in these regions. In conclusion, by using different approaches we identified the genetic cause for 38 patients. Although we still have a high number of patients without a genetic diagnosis, we hope with the continuous advancements in the field, more patients will be solved