High Diagnostic Yield and Clinical Utility of Whole Exome Sequencing Using an Automated Variant Prioriti S Ation System, EVIDENCE, for Patients with Suspected Genetic Disorders

Background: EVIDENCE, an automated variant prioritisation system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. Methods: DNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. Findings: EVIDENCE reported a total 245 variants in 216 (65·5%) of the 330 probands. The average number of organs involved per patient was 4·5 ± 5·0. After clinical reassessment and/or family member testing, 197 variants were identified in 172 probands (52·1%), including 116 novel variants. These variants were confirmed as being responsible for 147 genetic disorders. A total of 109 (55·3%) of the 197 variants were classified as pathogenic or likely to be pathogenic before, and 147 (74·6%) after, clinical assessment and/or family member testing. Factors associated with a variant being regarded as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores of a gene variant to the phenotype of the patient. Interpretation: This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 52·1% diagnostic yield. Funding: Institute for Information and Communications Technology Promotion (IITP) grant funded by the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis). Competing Interest Declaration: The authors declare no conflicts of interest. Ethical Approval: The study was approved by the Institutional Review Board for Human Research of the Asan Medical Center (IRB numbers: 2018-0574 and 2018-0180).