(194) Fetal fraction amplification dramatically increases PPV for 22q11.2 deletion syndrome in prenatal cell-free DNA screening

22q11.2 deletion syndrome occurs in approximately 1 in 2,000-4,000 births. Prenatal cell-free DNA screening (pcfDNA) can detect fetuses affected by deletions as small as 2.5 Mb. Fetal fraction amplification (FFA), which has been shown to yield an average fetal fraction (FF) in excess of 20%, may further enhance pcfDNA detection of these deletions. Positive predictive values (PPV) of pcfDNA screening for 22q11.2 microdeletion have been reported between 20%-50%. Here, we sought to describe the impact of FFA on the PPV of 22q11.2 microdeletion screening using a whole-genome sequencing (WGS)-based pcfDNA platform.

Study Design:

We retrospectively analyzed data from patients who underwent WGS-based pcfDNA screening with FFA (Prequel™, Myriad Genetics, Inc.) between 8/20-10/22. For screen-positive cases, pregnancy outcome data were requested via a routine HIPAA-compliant process. All samples with diagnostic confirmation were used to calculate PPV, defined as: true positives/(true positives + false positives). Confidence interval (CI) was estimated using the Exact Binomial Test.

Results:

Complete outcomes were obtained for 54 cases that screened positive for 22q11.2 microdeletion; 21 underwent molecular diagnostic testing. All 21 were confirmed as true positives, for a PPV of 100% (21/21; 95% CI 83.9%-100%). Among the 33 cases that declined molecular confirmation, 17 had ultrasound findings that are either strongly or moderately associated with 22q11.2 deletion syndrome (e.g., cardiac defects, polyhydramnios, skeletal defects, intrauterine growth restriction). The average FF of true positive samples was 23.0%. For screen-positive patients who declined diagnostic testing, the average FF was 21.6%.

Conclusion:

The increased FF levels conferred by FFA yield a PPV for 22q11.2 microdeletion higher than any previous studies have reported, and comparable to that for common autosomal trisomies. Because respective FF levels were comparable in patients with and without diagnostic confirmation, PPV is likely to be comparable in patients with and without diagnostic confirmation.