Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach
Maggie Westemeyer, Jennifer Saucier, Jody Wallace, Sarah A. Prins, Aparna Shetty, Meenakshi Malhotra, Zachary Demko, Christine M. Eng, Louis N. Weckstein, R. Boostanfar, Matthew Rabinowitz, Peter Benn, Dianne Keen‐Kim, Paul R. Billings
Abstract
PURPOSE: To present results from a large cohort of individuals receiving expanded carrier screening (CS) in the United States. METHODS: Single-gene disorder carrier status for 381,014 individuals was determined using next-generation sequencing (NGS) based CS for up to 274 genes. Detection rates were compared with literature-reported values derived from disease prevalence and carrier frequencies. Combined theoretical affected pregnancy rates for the 274 screened disorders were calculated. RESULTS: For Ashkenazi Jewish (AJ) diseases, 81.6% (4434/5435) of carriers identified did not report AJ ancestry. For cystic fibrosis, 44.0% (6260/14,229) of carriers identified had a variant not on the standard genotyping panel. Individuals at risk of being a silent spinal muscular atrophy carrier, not detectable by standard screening, comprised 1/39 (8763/344,407) individuals. For fragile X syndrome, compared with standard premutation screening, AGG interruption analysis modified risk in 83.2% (1128/1356) premutation carriers. Assuming random pairing across the study population, approximately 1/175 pregnancies would be affected by a disorder in the 274-gene screening panel. CONCLUSION: Compared with standard screening, NGS-based CS provides additional information that may impact reproductive choices. Pan-ethnic CS leads to substantially increased identification of at-risk couples. These data support offering NGS-based CS to all reproductive-aged women.