Application of a Severity Framework to 176 Genes on an Expanded Carrier Screening Panel [03G]

INTRODUCTION: Disease severity is considered to be an important factor for inclusion of diseases on expanded carrier screening (ECS) panels. Evaluating severity requires an objective, systematic method. Here, we applied a validated algorithm that objectively categorizes disease severity into one of four categories—profound, severe, moderate, and mild—to 176 genes on a clinically available ECS panel. METHODS: Eight genetic counselors (GCs) working in pairs, followed by four medical geneticists (MDs) working in pairs, applied the algorithm to subsets of the 176 genes. 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 after collaborative review. Final severity classifications were 68 (39%) profound, 71 (40%) severe, 36 (20%) moderate, and one (1%) mild. No classification biases were detected within the GC or MD pairs. CONCLUSION: This study illustrates an approach to severity classification for large sets of Mendelian genes. The observed level of initial discordance demonstrates the complexity of severity and underscores the importance of collaboration involving multiple clinicians. Severity classification, in addition to other factors suggested by ACOG, is an important factor for laboratories to consider as they aim to design clinically valid ECS panels.