The robust bioinformatics pipeline and comprehensive clinical review of patients with genetic disorders significantly improve overall diagnosis by exome sequencing

Background and Aim : In the recent years, whole-exome sequencing (WES) has become a common test to tackle the challenge of diagnosing inherited diseases. However, analysis of WES data is a hurdle ahead of clinicians as it needs an interdisciplinary collaboration between computer programmers and geneticists. Methods : We collected raw WES data along with clinical records of 13 undiagnosed patients with a suspected genetic disease. The clinical was reviewed by an experienced genetic counsellor and a medical geneticist to specify a list of potential phenotypes for each patient. We then created an automated WES data analyser program, called WEDA, which can perform the WES analysis of multiple cases in parallel and gives a short list of phenotype-related variants that could be clinically important. Briefly, WEDA maps read to the reference genome, then finds variants and annotates them. Finally, WEDA filters variants based on their frequency in populations and the patient phenotype. The candidate variants were classified based on ACMG guidelines.Results : Our improved re-analysis pipeline was able to identify at least one clinically relevant variant in 85% of previously undiagnosed cases among which 54% had a variant of unknown significance (VUS) and 31% had a pathogenic/likely pathogenic variant. We found that 71% of the VUSs could be reclassified as likely pathogenic if the familial co-segregation or de novo status of the variant is confirmed by the Sanger sequencing. We also discovered 13 novel variants in disease causing genes that have not been previously reported. Conclusion : Comprehensive bioinformatics and clinical re-analysis of patients with exome negative data improved the diagnosis rate by at least 31%. Our re-analysis could save up to 70,000,000 IRR (~$500) for the undiagnosed patients who are referred for re-sequencing. Overall, we believe that a robust bioinformatics pipeline hand in hand with an experienced team of clinicians and geneticists can significantly increase the rate of diagnostic success in patients undergoing whole exome sequencing.

کلیدواژه ها:

Whole exome sequencing ، clinical review ، reanalysis ، undiagnosed disease