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

BackgroundSeverity 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). MethodsEight 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. ResultsUpon 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 ACOGs four severity criteria. ConclusionThis 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. Whats already known about this topic?O_LIDisease severity is an important consideration for disease inclusion on expanded carrier screening panels. C_LIO_LIAn algorithm that objectively classifies diseases into severity categories has been published and validated. C_LI What does this study add?O_LI176 genes were classified into severity categories. C_LIO_LIThe algorithm was used to bring clarity to American College of Obstetricians and Gynecologists (ACOGs) severity criteria that are not easily interpretable. C_LIO_LI170 of 176 genes met at least one of ACOGs severity criteria. C_LI Data Availability StatementThe data that support the findings of this study have been completely reported in this manuscript and shared in the Figures and Supplementary Material.