Clinical outcome of subchromosomal events detected by whole‐genome noninvasive prenatal testing

Abstract

ObjectiveA novel algorithm to identify fetal microdeletion events in maternal plasma has been developed and used in clinical laboratory‐based noninvasive prenatal testing. We used this approach to identify the subchromosomal events 5pdel, 22q11del, 15qdel, 1p36del, 4pdel, 11qdel, and 8qdel in routine testing. We describe the clinical outcomes of those samples identified with these subchromosomal events.MethodsBlood samples from high‐risk pregnant women submitted for noninvasive prenatal testing were analyzed using low coverage whole genome massively parallel sequencing. Sequencing data were analyzed using a novel algorithm to detect trisomies and microdeletions.ResultsIn testing 175 393 samples, 55 subchromosomal deletions were reported. The overall positive predictive value for each subchromosomal aberration ranged from 60% to 100% for cases with diagnostic and clinical follow‐up information. The total false positive rate was 0.0017% for confirmed false positives results; false negative rate and sensitivity were not conclusively determined.ConclusionNoninvasive testing can be expanded into the detection of subchromosomal copy number variations, while maintaining overall high test specificity. In the current setting, our results demonstrate high positive predictive values for testing of rare subchromosomal deletions. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Trial by Dutch laboratories for evaluation of non‐invasive prenatal testing. Part I—clinical impact

“…In such cases, decisions on informing and advising couples were taken after multidisciplinary discussions between lab specialists, clinical geneticists and maternal–fetal medicine specialists. NIPT data on the occurrence of these anomalies in a population with an increased risk based on the FCT are slowly emerging 31, 32. In our study, 31% of the chromosomal abnormalities found were other than trisomy 21, 13 or 18.…”

Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG)

“…6 Recently, select microdeletion syndromes and smaller copy-number changes, as well as other autosomal aneuploidies, have been added by some laboratories as additional screening options. 7,8 Various factors affect the accuracy of NIPS results, including confined Disclaimer: ACMG Clinical Laboratory Practice Resources are developed primarily as an educational tool for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these practice resources is voluntary and does not necessarily assure a successful medical outcome.…”

Cell-free DNA testing for 22q11.2 deletion syndrome: appraising the viability, effectiveness and appropriateness of screening

“…Only one other commercial provider has published its experience with microdeletion screening 7 , while another presented data at the most recent meeting of the International Society for Prenatal Diagnosis 8 (Table 1). It is disappointing that, despite a combined total of more than 200 000 women undergoing microdeletion screening in these three studies, we still lack the basic performance metrics of sensitivity and negative predictive value for 22q11.2 DS in clinical practice.…”

“…In this present study, only two maternal carriers were suspected (one confirmed with genetic testing, and the other suspected on clinical findings). In another recent study that used a random whole-genome sequencing method, 20 of 32 high-risk calls involved a suspected maternal component 7 . These unexpected maternal findings clearly pose ethical implications if widespread screening in the low-risk population is to be considered seriously.…”