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Next-Generation DNA Sequencing: Improving the Accuracy of Routine Carrier Screening [286]

INTRODUCTION: To evaluate the clinical efficacy of next-generation sequencing for carrier screening for professional society-recommended disorders across a range of ethnicities. It is often difficult to ascertain a patient's true race or ethnicity to determine the appropriate tests to offer. Consequently, a growing number of physicians offer screening for the same disorders to all patients, regardless of ethnicity. Traditional screening assays have reasonable detection rates in high-risk populations but are suboptimal for patients of low-risk or mixed ethnicities, resulting in a large number of low-risk patients receiving screening with low detection rates. In contrast, next-generation sequencing more accurately determines carrier status because it is not limited to a small mutation set. METHODS: Using next-generation sequencing, carrier status was evaluated by Good Start Genetics for up to 14 disorders, as ordered by physicians, for patients seen at several fertility centers across the country. RESULTS: A total of 4,894 patients from six in vitro fertilization centers were screened, representing a multitude of unique ethnicity combinations. A total of 196 disease-causing mutations were identified. Twelve percent of these mutations would not have been detected by traditional genotyping assays. Moreover, 43% of pathogenic mutations were found in patients who did not identify as the corresponding high-risk ethnicity. CONCLUSION: Carrier screening is often ordered outside of the ethnicity-based guidelines. In this cohort, next-generation sequencing found 84 carriers that did not identify as the “high-risk” ethnicity. Traditional genotyping assays are not sufficient in centers routinely testing individuals of all ethnicities. Next-generation sequencing provides a more comprehensive determination of carrier status regardless of patient ethnicity.