Howard Cuckle

Cell-free DNA Analysis for Noninvasive Examination of Trisomy

BACKGROUND Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations. METHODS In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Downs syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13. RESULTS Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001). CONCLUSIONS In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).

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. Clinical trials have demonstrated the efficacy of NIPT for Down and Edwards syndromes, and possibly Patau syndrome, in high‐risk women. Universal NIPT is not cost‐effective, but using NIPT contingently in women found at moderate or high risk by conventional screening is cost‐effective. Positive NIPT results must be confirmed using invasive techniques. Established screening, fetal ultrasound and invasive procedures with microarray testing allow the detection of a broad range of additional abnormalities not yet detectable by NIPT. NIPT approaches that take advantage of SNP information potentially allow the identification of parent of origin for imbalances, triploidy, uniparental disomy and consanguinity, and separate evaluation of dizygotic twins. Fetal fraction enrichment, improved sequencing and selected analysis of the most informative sequences should result in tests for additional chromosomal abnormalities. Providing adequate prenatal counseling poses a substantial challenge given the broad range of prenatal testing options now available. Copyright

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

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Prenatal Diagnosis Unit, Institute of Gynecology, Obstetrics and Neonatology, Hospital Clinic, Maternitat Campus, University of Barcelona Medical School, Catalonia, Spain Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, New York, NY, USA Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO, USA Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Prenatal Screening Unit, Clinical Biochemistry Department, Barking Havering & Redbridge University Hospitals, King George Hospital, Goodmayes, UK Genetics Program, North York General Hospital, Toronto, ON, Canada Department of Mathematics and Statistics, University of Plymouth, Plymouth, UK Prenatal Diagnosis Unit, Genetic Institute, Sourasky Medical Center, Tel Aviv, Israel *Correspondence to: Peter Benn. E-mail: benn@nso1.uchc.edu This Statement replaces the January 2011 Statement (Prenatal Diagnosis 2011;31:519–522) and the Rapid Response Statement (Prenatal Diagnosis 2012;32:1–2).

Prenatal Detection of Down Syndrome using Massively Parallel Sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Prenatal Diagnosis Unit, Institute of Gynecology, Obstetrics and Neonatology, Hospital Clinic, Maternitat Campus, University of Barcelona Medical School, Catalonia, Spain Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, New York, NY, USA Department of Obstetrics and Gynecology, University of Calgary, Calgary, AB, Canada Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO, USA Laboratory for Infectious Diseases and Perinatal Screening, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Prenatal Screening Unit, Clinical Biochemistry Department, Barking Havering and Redbridge University Hospital, King George Hospital, Goodmayes, UK Department of Mathematics and Statistics, University of Plymouth, Plymouth, UK Prenatal Diagnosis Unit, Genetic Institute, Sourasky Medical Center, Tel Aviv, Israel *Correspondence to: Peter Benn. E-mail: benn@nso1.uchc.edu

Estimates of penetrance for recurrent pathogenic copy-number variations.

Purpose:Although an increasing number of copy-number variations are being identified as susceptibility loci for a variety of pediatric diseases, the penetrance of these copy-number variations remains mostly unknown. This poses challenges for counseling, both for recurrence risks and prenatal diagnosis. We sought to provide empiric estimates for penetrance for some of these recurrent, disease-susceptibility loci.Methods:We conducted a Bayesian analysis, based on the copy-number variation frequencies in control populations (n = 22,246) and in our database of >48,000 postnatal microarray-based comparative genomic hybridization samples. The background risk for congenital anomalies/developmental delay/intellectual disability was assumed to be ~5%. Copy-number variations studied were 1q21.1 proximal duplications, 1q21.1 distal deletions and duplications, 15q11.2 deletions, 16p13.11 deletions, 16p12.1 deletions, 16p11.2 proximal and distal deletions and duplications, 17q12 deletions and duplications, and 22q11.21 duplications.Results:Estimates for the risk of an abnormal phenotype ranged from 10.4% for 15q11.2 deletions to 62.4% for distal 16p11.2 deletions.Conclusion:This model can be used to provide more precise estimates for the chance of an abnormal phenotype for many copy-number variations encountered in the prenatal setting. By providing the penetrance, additional, critical information can be given to prospective parents in the genetic counseling session.Genet Med 2013:15(6):478–481

First-trimester maternal serum PP13 in the risk assessment for preeclampsia

OBJECTIVE The objective of the study was to determine whether first-trimester maternal serum placental protein 13 (PP13) concentrations can be used in the risk assessment for preeclampsia. STUDY DESIGN This case-control study included 50 patients with preeclampsia and 250 patients with normal pregnancies. Samples were collected between 8 and 13 weeks of gestation. Serum PP13 concentrations were measured by immunoassay and expressed as medians and multiples of the median (MoM) for gestational age. Sensitivity and specificity were derived from receiver-operating characteristic curve analysis. RESULTS (1) Serum PP13 concentration in the first trimester was significantly lower in patients who developed preterm and early-onset preeclampsia than in those with normal pregnancies; and (2) at 80% specificity, a cutoff of 0.39 MoM had a sensitivity of 100% for early-onset preeclampsia and 85% for preterm preeclampsia. CONCLUSION Maternal serum first-trimester PP13 appears to be a reasonable marker for risk assessment for preterm preeclampsia but a weak marker for severe preeclampsia at term, and ineffective for identifying mild preeclampsia at term.

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

President President-Elect Past President Secretary Treasurer Lucas Otano MD, PhD (Argentina) Ignatia B. Van den Veyver MD (USA) Jan M.M. van Lith MD, PhD (Netherlands) Louise Wilkins-Haug MD (USA) Antoni Borrell MD, PhD (Spain) Directors Peter Benn PhD, DSc (USA) Lyn Chitty PhD (UK) Rossa Chiu (Hong Kong) Roland Devlieger MD, PhD (Belgium) Sylvie Langlois MD, CCMG (Canada) Anthony O. Odibo MD, MSCE (USA) R. Doug Wilson MD, Msc, FRCSC (Canada) Yuval Yaron MD (Israel) Diana W. Bianchi MD, ex officio (USA) Position Statement from the Chromosome Abnormality Screening Committee on Behalf of the Board of the International Society for Prenatal Diagnosis

Maternal cfDNA screening for Down syndrome – a cost sensitivity analysis

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.

First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia.

Please cite this paper as: Wortelboer E, Koster M, Cuckle H, Stoutenbeek P, Schielen P, Visser G. First‐trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early‐onset pre‐eclampsia. BJOG 2010;117:1384–1389.

Contingent screening for Down syndrome—results from the FaSTER trial

Comparison of contingent, step‐wise and integrated screening policies.