67 Multicenter prospective study of SNP-based cfDNA for 22q11.2 deletion in 18,289 pregnancies with genetic confirmation

Abstract

Cell free DNA (cfDNA) screening for pathogenic copy number variants (CNV) such as 22q11.2 deletion syndrome (22q11.2DS) is clinically available. Data on test performance are limited. we report on the performance of SNP-based cfDNA in a large prenatal cohort. We hypothesized that SNP-based cfDNA can detect 22q11.2DS deletions that are >500kb. Patients who had SNP-based cfDNA for aneuploidy and 22q11.2DS were recruited at 21 centers in 6 countries. Genetic confirmation was obtained for all pregnancies from prenatal or newborn DNA samples. All microdeletions larger than 500kb associated with 22q11.2DS were included in the test performance analysis, including the 2.5-3Mb LCR22A-D classic deletion as well as smaller nested deletions. An updated cfDNA algorithm that was blinded to pregnancy outcome was also evaluated. Of 20,887 women enrolled, 18,289 (87.6%) had both cfDNA and DNA confirmation results for 22q11.2DS. Mean maternal age and gestational age at enrollment were 33.7 years and 13.3 weeks, respectively. Twelve 22q11.2DS cases were identified by prenatal (n=3) or postnatal (n=9) testing, yielding a cohort prevalence of 1:1524. Deletion sizes are detailed in the table below. The screen positive rate of cfDNA for 22q11.2DS was 0.2% (37/18,289). Sensitivity was 75.0% (95% CI: 50.5, 99.5); specificity was 99.84% (95% CI: 99.79, 99.90); and PPV was 24.3% (95% CI: 10.5, 38.2). Sensitivity, specificity and PPV were all higher using the updated algorithm (83.3%; 99.95%, and 52.6%, respectively) and the screen positive rate was significantly lower (0.1%; p=0.0004). There were no cases of 22q11.2DS in the 1.46% of cases without results (“no call” cases). In a prospective cohort of 18,289 pregnancies with genetic confirmation, SNP-based cfDNA screening for 22q11.2DS had high sensitivity and specificity and detected both classic and nested deletions with a PPV greater than 50% using an updated algorithm.