The origins of aneuploidy research consortium.

The presence of high levels of aneuploidy in oocytes and early embryos and their fate is of considerable scientific and clinical importance. The Origins of Aneuploidy Research Consortium (OARC) was established to promote interdisciplinary communication and collaborative research into this topic. Under the umbrella of OARC, a series of papers has now been published in this Special Issue of Prenatal Diagnosis.

The promise of gene therapy.

Purpose Of Review: The promise of gene therapy performed in the preimplantation and prenatal periods of pregnancy is rapidly becoming a reality. New technologies capable of making designed changes in single nucleotides make germline gene therapy possible. The article reviews the ethical and technical challenges of germline gene therapy.

Cell-free DNA screening for fetal aneuploidy as a clinical service.

Non-invasive prenatal testing (NIPT) through the analysis of cell free (cf)DNA is revolutionizing prenatal screening for fetal aneuploidy. Current methods used in clinical practice include shotgun massively parallel sequencing (s-MPS); targeted (t-MPS); and an approach that takes advantage of single nucleotide polymorphism (SNP) differences between mother and fetus. Efficacy of cfDNA testing for the common autosomal trisomies far exceeds that of conventional screening.

Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort.

Objective: To estimate performance of a single-nucleotide polymorphism-based noninvasive prenatal screen for fetal aneuploidy in high-risk and low-risk populations on single venopuncture.

Methods: One thousand sixty-four maternal blood samples from 7 weeks of gestation and beyond were included; 1,051 were within specifications and 518 (49.3%) were low risk.

Replacing the combined test by cell-free DNA testing in screening for trisomies 21, 18 and 13: impact on the diagnosis of other chromosomal abnormalities.

Objective: To estimate the proportion of other chromosomal abnormalities that could be missed if combined testing was replaced by cell-free (cf) DNA testing as the method of screening for trisomies 21, 18 and 13.

Methods: The prevalence of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities was examined in pregnancies undergoing first-trimester combined screening and chorionic villus sampling (CVS).

Results: In 1,831 clinically significant chromosomal abnormalities in pregnancies with combined risk for trisomies 21, 18 and 13≥1:100, the contribution of trisomies 21, 18 or 13, sex chromosome aneuploidies, triploidy and other chromosomal abnormalities at high risk of adverse outcome was 82.

The Future of Prenatal Diagnosis and Screening.

The future of prenatal diagnosis and screening lies in developing clinical approaches and laboratory technologies applicable to genetic analyses and therapeutic interventions during embryonic development.

Paternity balancing.

Background: Gestational carriers and egg donors have been used by 'traditional' and now increasingly, gay couples. Three gay male couples, all using egg donors and gestational carriers with semen from both partners, had triplets. All desired reductions to twins for the standard medical indications, but requested, if reasonably possible, to have twins with one fathered by each partner.

Detection of genetic abnormalities by using CVS and FISH prior to fetal reduction in sonographically normal appearing fetuses.

Objective: To examine the ability of chorionic villus sampling (CVS) and fluorescence in situ hybridization (FISH) to detect aneuploidy before first trimester fetal reduction (FR) in sonographically normal-appearing fetuses.

Methods: A retrospective review of 470 patients referred to our unit for FR from January 2007-March 2011. Prenatal diagnosis was offered to all.

Non-invasive prenatal testing for aneuploidy: current status and future prospects.

Non-invasive prenatal testing (NIPT) for aneuploidy using cell-free DNA in maternal plasma is revolutionizing prenatal screening and diagnosis. We review NIPT in the context of established screening and invasive technologies, the range of cytogenetic abnormalities detectable, cost, counseling and ethical issues. Current NIPT approaches involve whole-genome sequencing, targeted sequencing and assessment of single nucleotide polymorphism (SNP) differences between mother and fetus.

Maternal cfDNA screening for Down syndrome--a cost sensitivity analysis.

Objective: This study aimed to determine the principal factors contributing to the cost of avoiding a birth with Down syndrome by using cell-free DNA (cfDNA) to replace conventional screening.

Methods: A range of unit costs were assigned to each item in the screening process. Detection rates were estimated by meta-analysis and modeling.

Nearly a third of abnormalities found after first-trimester screening are different than expected: 10-year experience from a single center.

Objective: This study aimed to assess the efficacy of first-trimester aneuploidy screening in a single clinical setting.

Methods: Maternal age, nuchal translucency, and maternal serum levels of pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin comprised first-trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18.

Reproductive decisions after fetal genetic counselling.

A broad range of testing modalities for fetal genetic disease has been established. These include carrier screening for single-gene mutations, first-trimester and second-trimester screening for chromosome abnormalities and open neural-tube defects, prenatal diagnosis by means of chorionic villus sampling and amniocentesis, and preimplantation genetic diagnosis. Reproductive decisions before and after fetal genetic counselling represent the culmination of a dynamic interaction between prospective parents, obstetrician and genetic counsellor.

Digital PCR for noninvasive detection of aneuploidy: power analysis equations for feasibility.

Objective: To determine the feasibility of digital PCR analysis for noninvasive prenatal diagnosis of trisomy 21.

Methods: Through power equations, we modeled the number of wells necessary to determine the feasibility of digital PCR as a practical method for trisomy 21 risk assessment.

Results: The number of wells needed is a direct correlate of the ability to isolate free fetal DNA.

Increased nuchal translucency in the presence of normal chromosomes: what's next?

Purpose Of Review: First trimester screening is presently offered to all pregnant women as a means of prenatal screening for Down syndrome, trisomy 18, and trisomy 13. Nuchal translucency measurement is a fundamental component of the screening protocol. A woman whose fetus' nuchal translucency is greater than the 95th percentile is also at increased risk for a multiplicity of other adverse pregnancy and pediatric outcomes, and as a consequence, counseling of patients about their testing options and range of pregnancy outcomes has become complex and difficult.

Genetic assessment following increased nuchal translucency and normal karyotype.

Objective: The objective of this study was to assess the first formal approach for monitoring genetic/developmental syndromes associated with the presence of an increased nuchal translucency (NT) thickness (>3 mm) in the first trimester of pregnancy.

Methods: Multiple technologies-a DNA chip using the APEX technology, qPCR, microfluidic PCR, and sequencing-were applied to assay 310 mutations across five conditions-Noonan syndrome, congenital adrenal hyperplasia, spinal muscular atrophy (SMA), DiGeorge syndrome, and Smith-Lemli Opitz syndrome.

Results: We report the results of assessing the first 120 patients in which 8 cases of Noonan syndrome were detected as well as an unusually high rate of heterozygosity for SMA.

First-trimester genetic counseling: perspectives and considerations.

As first trimester screening has assumed an increasingly dominant role in the obstetric care of prospective parents, the need for genetic counseling has also increased. There are several challenges related to first trimester screening; foremost among them is the need to distinguish between screening and diagnosis. Additional challenges include the need to discuss not only Down syndrome but cardiac defects, developmental/genetic syndromes, adverse pregnancy outcomes, and preeclampsia.

Impact of quality of nuchal translucency measurements on detection rates of trisomies 13 and 18.

Objective: To determine the relative contribution of nuchal translucency (NT) to the biochemical detection rates of combined screening for trisomies 13 and 18 in two healthcare systems practicing different quality-control systems of nuchal measurement.

Methods: De-identified data collected from the Fetal Medicine Foundation in the United Kingdom and laboratory data from NTD laboratories in the United States were compared for detection rate and false-positive rate (FPR) for combined trisomies 13 and 18 screening and were subcategorized by biochemical only and biochemistry combined with NT measurement.

Results: US and UK biochemical detection rates were virtually identical: 83% for a FPR of 1.

Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial.

This prospective randomized controlled pilot trial was designed to evaluate whether prescreening embryos for aneuploidy can improve clinical outcomes in infertile patients undergoing IVF, without limiting to poor prognosis patients. Although there was no statistically significant improvement in live birth rates or implantation rates in this pilot study, there was a trend toward improved clinical outcomes, indicating that future multicenter randomized trials are needed.