Evaluation and classification of severity for 176 genes on an expanded carrier screening panel

Abstract Background Severity is an important factor for inclusion of diseases on expanded carrier screening (ECS) panels. Here, we applied a validated algorithm that objectively classifies diseases into severity categories to 176 genes on a clinically available ECS panel. We then mapped disease traits from the algorithm to severity-related criteria cited by the American College of Obstetricians and Gynecologists (ACOG). Methods Eight genetic counselors (GCs), followed by four medical geneticists (MDs), applied the algorithm to subsets of the 176 genes. MDs and GCs then determined which disease traits met ACOG severity criteria. Results Upon initial GC and MD review, 107/176 genes (61%) and 133/176 genes (76%), respectively, had concordant classifications, with consensus reached for all genes. Final severity classifications were 68 (39%) profound, 71 (40%) severe, 36 (20%) moderate, and one (1%) mild. The vast majority of genes (170 out of 176) met at least one of ACOG’s four severity criteria. Conclusion This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of an algorithm. Further, it clarified and operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation across laboratories. What’s already known about this topic? Disease severity is an important consideration for disease inclusion on expanded carrier screening panels. An algorithm that objectively classifies diseases into severity categories has been published and validated. What does this study add? 176 genes were classified into severity categories. The algorithm was used to bring clarity to American College of Obstetricians and Gynecologist’s (ACOG’s) severity criteria that are not easily interpretable. 170 of 176 genes met at least one of ACOG’s severity criteria. Data Availability Statement The data that support the findings of this study have been completely reported in this manuscript and shared in the Figures and Supplementary Material.