Carrier Screening With Next-Generation Sequencing Detects Common, Uncommon, and Novel Mutations [288]

INTRODUCTION: Carrier screening for specific genetic disorders is recommended by the American College of Obstetricians and Gynecologists, the American College of Medical Genetics, and societies representing the Ashkenazi Jewish population. As a result of cost and technologic constraints, traditional screening assays look for only the most common mutations within a gene. This yields reasonable detection rates in specific populations but is suboptimal for patients of other, mixed, or uncertain ethnicities. Our objective was to evaluate the clinical effectiveness of next-generation sequencing in screening for carriers of society-recommended disorders. METHODS: A high-throughput and proprietary methodology (including multiplex gene capture, next-generation sequencing, and computational analysis) was used to test samples from patients representing a broad spectrum of ethnicities. Carrier status was evaluated for up to 14 disorders, as ordered by physicians, for 39,972 patients from in vitro fertilization centers. Clinical reports were issued on the presence or absence of disease-causing mutations in genes associated with society-recommended disorders. RESULTS: Among the 39,972 clinical samples evaluated, 1,948 (4.9%) patients were found to be carriers of 305 distinct pathogenic mutations across the 14 disorders. Of the 1,948 carriers detected, 16.3–22.4% would have been missed by other major laboratories using traditional carrier screening assays, providing patients with a false sense of reassurance in their negative test result. CONCLUSION: As a result of the vast number of pathogenic mutations detectable by next-generation sequencing, it is possible to more comprehensively evaluate carrier status. This yields higher detection rates and hence reduced residual risk for each disorder, overall resulting in fewer missed carriers than traditional carrier screening tests.