ACMG statement on noninvasive prenatal screening for fetal aneuploidy

Abstract

The American College of Medical Genetics and Genomics (ACMG) believes that the application of genetic technology, particularly when used in the prenatal setting, needs to be supported by prospective clinical trials and considered carefully before its incorporation into routine clinical care. The ACMG has previously published guidelines on prenatal screening for Down syndrome, which have successfully assisted health-care providers and their patients during pregnancy. 1One of the major breakthroughs in obstetrical care was the advent of prenatal genetic diagnosis, initially by amniocentesis in the second trimester of pregnancy. Subsequently, chorionic villus sampling during the first trimester allowed for earlier diagnosis and management. However, the potential risk of fetal loss secondary to an invasive procedure has driven the search for noninvasive approaches for genetic screening and diagnosis. Until recently, noninvasive screening for aneuploidy relied on either the measurement of maternal serum analytes and/or ultrasonography with positive screen rates of ~5% and detection rates of 50-95%, depending on the screening strategy utilized. More recent advances in genomics and genomic technologies have resulted in the development of a noninvasive prenatal screening (NIPS) test using cell-free fetal DNA sequences isolated from a maternal blood sample.2-6 About 10% of DNA in maternal serum is of fetal origin; 4,7,8 this has been used for prenatal Rh determination and gender identification. Using nextgeneration sequencing platforms, millions of amplified genetic fragments can be sequenced in parallel (massively parallel sequencing). Platforms differ according to whether amplified regions throughout the genome, chromosome-specific regions, or single-nucleotide polymorphisms are the targets for sequencing. Furthermore, by using powerful bioinformatics tools, differences between maternal and fetal sequences and dosage differences in identical sequences or a reference chromosome can be determined and used for noninvasive screening for fetal aneuploidy. 9,10 Although studies are promising and demonstrate high sensitivity and specificity with low false-positive rates, there are limitations to NIPS. Specificity and sensitivity are not uniform for Noninvasive assessment of the fetal genome is now possible using next-generation sequencing technologies. The isolation of fetal DNA fragments from maternal circulation in sufficient quantity and sizes, together with proprietary bioinformatics tools, now allows patients the option of noninvasive fetal aneuploidy screening. However, obstetric care providers must become familiar with the advantages and disadvantages of the utilization of this approach as analysis of cell-free fetal DNA moves into clinical practice. Once informed, clinicians can provide efficient pretest and posttest counseling with the goal of avoiding patient harm. It is in the public's best interest that test results contain key elements and that laboratories adhere to established quality control and proficiency te...

Trends in Invasive Prenatal Diagnosis: Effect of Sequential Screening and Noninvasive Prenatal Testing

“…It is important to note, however, that despite the near-diagnostic accuracy of NIPT, it remains a screening test [23]. Indeed, both NIPT and other screening tests still require confirmatory diagnostic invasive testing prior to any decision involving subsequent prenatal care or pregnancy termination [12,24]. …”

Uptake of Noninvasive Prenatal Testing in Chinese Women following Positive Down Syndrome Screening

“…Ideally, NIPT is incorporated into the current screening program for Down syndrome. Guidelines on the proper use of NIPT have been published by various authorities [21,22,23,24]. Whatever care model or cutoff points after a conventional screening test used [18,25], providing adequate information including benefits and limitations of NIPT and obtaining informed consent are very important [26,27].…”

Expanding diagnostic testing beyond cytogenetics: Implications for birth defects research and surveillance

“…The best results to date have shown a nearly 100% detection rate of trisomy 21 with a false-positive rate of less than 1%, and detection rates for trisomies 13 and 18 are now approaching those levels; however, it must be noted that these validation studies have been done in high risk pregnancies, not as population-based screenings (reviewed in Langlois et al, 2013). Because of this caveat and the varying detection rates, cffDNA analysis is currently being offered only as a screening test rather than as a diagnostic test, and results indicative of an aneuploidy require validation through karyotype analysis of cells collected by means of amniocentesis or CVS (Gregg et al, 2013). Further down the road is the prenatal use of NGS and cffDNA to obtain whole genome and exome fetal DNA sequences for prenatal diagnosis of a myriad of genetic conditions; however, this technology is still in the research phase and not yet clinically available (Kitzman et al, 2012).…”