High positive predictive value 22q11.2 microdeletion screening by prenatal cell-free DNA testing that incorporates fetal fraction amplification

Abstract

Objective: 22q11.2 deletion syndrome (DS) is a serious condition with a range of features. The small microdeletion causing 22q11.2DS makes it technically challenging to detect using standard prenatal cfDNA screening. Here, we assess 22q11.2 microdeletion clinical performance by a prenatal cfDNA screen that incorporates fetal fraction (FF) amplification. Methods: The study cohort consisted of patients who received Prequel (Myriad Genetics, Inc.), a prenatal cfDNA screening that incorporates FF amplification, and met additional eligibility criteria. Pregnancy outcomes were obtained via a routine process for continuous quality improvement. Samples with diagnostic testing results were used to calculate positive predictive value (PPV). Results: 379,428 patients met study eligibility criteria, 76 of whom were screen-positive for a de novo 22q11.2 microdeletion. 22 (29.7%) had diagnostic testing results available, and all 22 cases were confirmed as true positives, for a PPV of 100% (95% CI 84.6%–100%). This performance was based on cases that ranged broadly across FF (5.9%–41.1%, mean 23.0%), body mass index (22.3–44.8, mean 29.9), and gestational age at testing (10.0w–34.6w, median 12.7w). Ultrasound findings in screen-positive pregnancies were consistent with those known to be associated with 22q11.2DS. Conclusion: 22q11.2 microdeletion screening that incorporates FF amplification demonstrated high PPV across both general and high-risk population cohorts.