Diagnostic performance of automated streamlined, daily updated, exome analysis in patients with delayed development

초록

Introduction Diagnostic yield of exome sequencing (ES) varies from 30%-50% for patients with mild to severe developmental delay (DD)/intellectual disability (ID). Routine retrospective reanalysis of data from undiagnosed have been increasing the total diagnostic yield by 10-15%. Here, we performed proband-only ES in 1065 patients with DD/ID and applied a prospective, daily reanalysis automated pipeline in patients without clinically significant variants to facilitate diagnosis. Methods The study included 1065 consecutive patients from 1056 non-consanguineous unrelated families from 10 multi-medical centers in South Korea between April 2018 to August 2021. ES data was analysed by daily automatically updated databases, variant classification, and symptom similarity scoring system. We implemented daily reanalysis pipeline in April 2019. For patients with no clinically significant variants, only a VUS, potential compound heterozygous variants with one P/LP variant and one VUS, or multiple VUS reported, EVIDENCE was run on a daily basis with new annotations for the entire study period for re-analysis. Results At initial analysis, 401 patients from 1056 unrelated families (38.0%, 401/1056 families) had positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of additional diagnostic 30 variants in 27 patients (2.6%), which increased our molecular diagnostic yield to 40.5% (428/1056 families). The 276 Mendelian diseases-gene were found in the 428 families: autosomal dominant (N = 194, 70.3%), autosomal recessive (N = 53, 19.2%), X-linked (N = 23, 8.3 %), and autosomal dominant and/or recessive (N=6, 2.2%). Most genes were reported once (199 genes), twice (48 genes) or three times (11 genes). Among the 27 patients with diagnosis by reanalysis, 22 patients were diagnosed with different 21 diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.1 ± 0.8 year, which has got shorter in the patients enrolled during the latter end of the study period. Even 6 patients were diagnosed with a new disease within 100 days of the first analysis. Conclusion As this study is the first to consider diagnostic and clinical utility of ES for a large, multi-centered cohort group of patients with DD/ID in South Korea, proband only ES could be useful in the genetic diagnosis of patients with DD/ID that have diverse genetic causes. Daily updated database and reanalysis system enhances the diagnostic performance in patients with DD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.