Single nucleotide polymorphism–based cell-free DNA prenatal screening for 22q11.2 deletion syndrome

Abstract

Nowadays, many prenatal cell-free DNA (cfDNA) testing providers offer additional screening for a panel of selected microdeletions.1Di Renzo G.C. Bartha J.L. Bilardo C.M. Expanding the indications for cell-free DNA in the maternal circulation: clinical considerations and implications.Am J Obstet Gynecol. 2019; 220: 537-542Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Individual microdeletions are much rarer in prevalence and usually present with variable phenotypes. Accordingly, there is less analytical validation and clinical trial data regarding cfDNA performance. Furthermore, the rarer the disease, the lower the positive predictive value (PPV) of cfDNA. Therefore, current evidence indicate that cfDNA for microdeletions should not be offered routinely.2Familiari A. Boito S. Rembouskos G. et al.Cell-free DNA analysis of maternal blood in prenatal screening for chromosomal microdeletions and microduplications: a systematic review.Prenat Diagn. 2021; 41: 1324-1331Crossref PubMed Scopus (3) Google Scholar Recently, Dar et al3Dar P. Jacobson B. Clifton R. et al.Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.Am J Obstet Gynecol. 2022; ([Epub ahead of print])Google Scholar assessed the performance of single nucleotide polymorphism (SNP)-based cfDNA prenatal screening for 22q11.2 deletion syndrome (22q11.2DS) in a large cohort study. This study included a total of 18,289 patients with comprehensive genetic confirmation obtained using fetal or newborn DNA samples. Using an updated algorithm, the authors reported a detection rate of 83.3%, a false positive rate of 0.05%, and a PPV of 52.6% (Figure) . They concluded that expansion of routine cfDNA screening to include screening for 22q11.2DS should be considered for all pregnant women. However, the study raises some important issues which should be addressed. There were 36 cases of common aneuploidies diagnosed in this study. Were these aneuploidies detected by the same SNP-based cfDNA test for 22q11.2DS? Were these patients offered the traditional cfDNA testing, targeting only common aneuploidies? If the 2 methodologies were different, 2 separate cfDNA tests would be needed to report the 2 different results. This might increase the cost. Although 10 patients had positive cfDNA results, only 3 had been offered invasive testing; 1 patient opted for termination of pregnancy (TOP) only because of fetal 22q11.2DS, and 2 opted for TOP because of additional structural anomalies. Seven patients did not chose prenatal confirmation and continued the pregnancy to term, although they received a positive result from the cfDNA screening that was conducted at ≤20 weeks’ gestation. These results indicate that the main purpose of the introduction of cfDNA for 22q11.2DiS is to enable early postnatal interventions aimed at improving the outcome. If this is the case, it does not seem cost-effective to screen for the 5 out of 12 cases with 22q11.2DS in a total of 18,289, considering the remaining 7 cases with fetal anomalies that would routinely be detected by invasive testing. Collectively, microdeletion syndromes account for 1% to 2% of all structurally normal pregnancies.4Srebniak M.I. Knapen M.F.C.M. Polak M. et al.The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies.Hum Mutat. 2017; 38: 880-888Crossref PubMed Scopus (21) Google Scholar In younger women, the risk for a significant deletion exceeds that for trisomy 21. Because most microdeletions are not detectable on ultrasound, a well-developed, genome-wide cfDNA test would be the ultimate solution. Performance of noninvasive prenatal screening for 22q11.2 deletion syndrome in the SMART studyAmerican Journal of Obstetrics & GynecologyPreviewThank you for your interest in our study.1 Although we agree that many individual microdeletions are rare when compared with the common aneuploidies, this is not the case for 22q11.2 deletion syndrome (22q11.2DS), which has a prevalence that is greater than either trisomy 13 or trisomy 18.1,2 We also agree that because microdeletions are rare, there is less analytical validation than for common aneuploidies. This is precisely what prompted the SMART study, which reported a sensitivity of 83% and a positive predictive value (PPV) of 52.6%, which is much higher than the PPV of traditional serum screening for trisomy 21 and other aneuploidies. Full-Text PDF