Prenatal Screening for 22q11.2 Deletion Using a Targeted Microarray-Based Cell-Free DNA Test

Abstract

Objective: To determine the performance of a targeted microarray-based cell-free DNA (cfDNA) test (Harmony Prenatal Test®) for the identification of pregnancies at increased risk for 22q11.2 deletion. Methods: Test performance was determined in 2 steps including a total of 1,953 plasma samples. Analytical validation was performed in 1,736 plasma samples. Clinical verification of performance was performed in an additional 217 prospectively ascertained samples from pregnancies with fetal deletion status determined by diagnostic testing. Results: Analytical sensitivity was 75.4% (95% CI: 67.1–82.2%) based on 122 samples with deletions ranging from 1.96 to 3.25 Mb. In 1,614 presumed unaffected samples, specificity was determined to be at least 99.5% (95% CI: 99.0–99.7%). In the clinical cohort, 5 of 7 samples from pregnancies affected with 22q11.2 deletion were determined to have a high probability of deletion. There were no false positive results in the 210 unaffected samples in this cohort. These clinical data are consistent with the performance demonstrated in the analytical validation. Conclusions: cfDNA testing using a targeted microarray-based technology is able to identify pregnancies at increased risk for 22q11.2 deletions of 3.0 Mb and smaller while maintaining a low false positive rate.

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

“…The introduction of TREC testing as part of newborn screening throughout the US and in other countries has accelerated the time when infants with 22q11.2del are diagnosed, and this will mean in more rapid and appropriate clinical interventions (Dorsey et al, 2017). Innovations in whole genome sequencing and DNA-based microarrays also make possible an accurate diagnosis of 22q11.2del in the developing fetus using maternal blood sampling (Yatsenko et al, 2015;Schmid et al, 2017). These non-invasive prenatal tests are very sensitive and have low false positive discovery rates (Ravi et al, 2018).…”

“…DiGeorge syndrome is first suggested following newborn screens for detecting the levels T-cell receptor excision circles (TRECs) as a measure of T cell output from the thymus ( Table 1) (Botto et al, 2003;Kobrynski and Sullivan, 2007;Mcdonald-Mcginn et al, 2015). Low TRECs can be an indicator of DiGeorge syndrome, with the diagnosis of 22q11.2del subsequently established by FISH or chromosomal microarray technologies (Kwan et al, 2014;Van Der Spek et al, 2015;Schmid et al, 2017;Ravi et al, 2018). The heterogeneous congenital problems for 22q11.2del patients arise from defective remodeling of the pharyngeal region during embryogenesis (Sullivan, 2004;Bassett et al, 2005;Kobrynski and Sullivan, 2007;Fung et al, 2015;Guna et al, 2015;Mcdonald-Mcginn et al, 2015;Baldini et al, 2016).…”

Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome

“…A new approach developed to determine fetal risk utilizes cell‐free DNA from maternal serum, an approach that limits the risk to the fetus. This effort has been developed to screen for aneuploidy and uses directed capture of DNA for analysis . This was recently piloted for 22q11.2del.…”

“…This effort has been developed to screen for aneuploidy and uses directed capture of DNA for analysis. 142 This was recently piloted for 22q11.2del. Additional efforts based on cell-free DNA from maternal serum have been developed that utilize single nucleotide polymorphism arrays and multiplex PCR.…”

DiGeorge syndrome chromosome region deletion and duplication: Prenatal genotype‐phenotype variability in fetal ultrasound and MRI

“…Until then, together, we propose health care providers to extend their familiarity with prenatal recognition of associated phenotypic features and suggest generously consideration of fetal genetic testing for DGS and dup22q11 syndrome. Therefore, we highly appreciate the opportunity of NIPT expanding to the detection of fetal microdeletion syndromes but strongly recommend its use to be considered alongside and only combined with fetal ultrasound to provide accurate prenatal counseling, shown in Figure . In conclusion, genotype‐phenotype correlation assessed by fetal molecular genetic analysis, fetal ultrasound, and/or MRI improves the understanding of the complex genetics underlying the DGCR and highly enhances prenatal diagnosis, screening and counseling for fetal DGS and dup22q11 syndrome.…”