Refining reproductive risk for FMR1 premutation carriers in the general obstetric population.

Female FMR1 premutation (FMR1 PM) carriers for fragile X syndrome (FXS) are at risk to have a child with FXS based on their CGG repeat size and AGG interruption number. Studies examining this risk in unselected populations of female PM carriers are lacking. This retrospective cohort study analyzed carrier status, CGG repeat length, AGG interruption result, and reproductive risk refinement in a population of female patients who underwent routine carrier screening for FXS. A total of 1536 PM carriers (0.43%) were identified, 95% of whom had between 55 and 90 CGG repeats. A number of 1334 carriers underwent AGG interruption testing. The majority had at least one AGG interruption and received a lower reproductive risk for FXS following AGG interruption testing (89% and 85%, respectively) as compared to their risk calculated based on CGG repeat size alone. The average change in risk across the population following AGG interruption testing was -3.4%, with a range from -50.8% to 48.9%. This article describes the range of CGG repeats and AGG interruptions in an unselected population of female PM carriers and suggests that most carriers would benefit from AGG interruption testing to refine their reproductive risk of having a child with FXS.

Clinical experience with multigene carrier panels in the reproductive setting.

OBJECTIVES: Expanded carrier testing is acknowledged as an acceptable strategy for carrier testing by the American College of Obstetrics and Gynecology. Limited studies have investigated positivity rates of expanded carrier panels. We describe our experience with 3 commercial laboratory panels varying in size from 3 to 218 disorders. METHODS: We reviewed outcomes for 3 multigene carrier screening panels: trio (3 diseases), standard (23 diseases), and global (218 diseases). All panels used targeted genotype analysis of preselected mutations via next-generation sequencing. We calculated positivity rates for each panel. RESULTS: Positivity rates were 7.2% for Preparent Trio, 13.2% for Preparent Standard, and 35.8% for Preparent Global. The most frequent positive results in the global panel were (in descending order): abnormal hemoglobin electrophoresis, familial Mediterranean fever, cystic fibrosis, fragile X, glucose-6-phosphate dehydrogenase deficiency, alpha-thalassemia, and nonsyndromic hearing loss. CONCLUSIONS: While genetic diseases are individually rare, they are cumulatively common. Our experience illustrates that, with a panel of 218 diseases, the likelihood of identifying a carrier can be as high as 36%. Understanding panel positivity rates is one important factor for providers when choosing the right test for their practice, setting appropriate expectations for patients, and planning for follow-up counseling.