Screening for Down syndrome – incidental diagnosis of other aneuploidies

Abstract

Objective Down syndrome screening programmes lead to the prenatal diagnosis of other chromosomal abnormalities, some of which would not be detected by the secondary use of cell-free (cf)DNA testing in screen positives. This study aims to assess the number of these incidental diagnoses.Method This study is a systematic review of the literature to identify large prospective screening studies that reported diagnoses other than trisomies 21 and 18.Results There were ten informative prospective studies in which a total of 1 500 999 women were screened, and there were 3689 aneuploidy cases detected in the screen positives. Trisomy 21 was estimated to comprise only 58% of detected aneuploidies, trisomies 21 and 18 comprised 72%, and the common trisomies -21, 18 and 13 -comprised 76%. Common trisomies and sex chromosome abnormalities, now included in all commercial cfDNA tests, were estimated to comprise 87% of aneuploidies in the Down syndrome screen positives. All these proportions were higher for second trimester protocols compared with those carried out wholly or partly in the first trimester.Conclusion Secondary use of cfDNA testing will lead to about one-fifth reduction in diagnoses, taking account of both undetectable aneuploidies and false-negatives. This loss might be overcome by contingent cfDNA testing.

Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis

“…However, it is important to recognize that all screening tests, including cfDNA testing, are not fully diagnostic and follow‐up confirmatory studies are necessary for positive screening results. In addition, screening only targets specific chromosomal imbalances and does not identify all of the abnormalities identifiable through invasive testing . When women receive screening for specific chromosome abnormalities, they should be informed about their risk for all detectable abnormalities, not just those included in the screening panel.…”

“…In addition, screening only targets specific chromosomal imbalances and does not identify all of the abnormalities identifiable through invasive testing. 6 When women receive screening for specific chromosome abnormalities, they should be informed about their risk for all detectable abnormalities, not just those included in the screening panel.…”

Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6,388 consecutive cases

“…Large-scale clinical studies and an updated meta-analysis comprehensively described the performance of cfDNA testing for the common trisomies—21, 18, and 13—and, to a lesser extent, for sex-chromosome anomalies (SCAs). 1 , 2 , 3 , 4 Independent lines of converging evidence suggest that a substantial fraction of clinically relevant aneuploidies is neglected by such a restricted detection scheme: (i) the common trisomies comprise only approximately 75% of aneuploidies detected by karyotyping in Down syndrome screen-positive cases, with 85% including the SCAs 5 ; (ii) registry data showed that 17% of clinically relevant anomalies would go undetected 6 ; and (iii) a review of 4,000 prenatal karyotype results revealed that 24% of the reported anomalies would have been overlooked. 7 …”

First trimester screening for Down syndrome using nuchal translucency, maternal serum pregnancy‐associated plasma protein A, free‐β human chorionic gonadotrophin, placental growth factor, and α‐fetoprotein

“…Multiple studies have suggested that cfDNA testing can be implemented by using it contingently following a first‐line conventional screening test . While the contingent model will result in a lower detection rate (DR) than routine stand‐alone cfDNA testing, as some Down syndrome cases will not be selected by the first‐line test, it will preserve the additional benefits of conventional screening in displaying adverse pregnancy outcome indicators and be cost‐effective . In order to incorporate cfDNA into the current screening system, an optimal first‐line screening test that can provide results in the first trimester is desired to facilitate timely further clinical follow‐up.…”