This technical standard was developed as a guide for laboratories performing prenatal screening for Down syndrome. It addresses 3 topics: second trimester (triple or quad), first trimester, including incorporation of nuchal translucency, and current directions in cell-free DNA screening. Analytic methods, clinical considerations, screening performance, guidelines for reporting second trimester, first trimester, integrated, contingent, and reflex screening tests for Down syndrome, are discussed. Individual laboratories are responsible for meeting the quality assurance standards described by the Clinical Laboratory Improvement Amendments, the College of American Pathologists, and other regulatory agencies, with respect to appropriate sample documentation, assay validation, general proficiency, and quality control measures.

Purpose: Workforce shortages are observed in many sectors of the economy, including clinical genomics laboratories. Although medical technologists are essential for the primary functions of laboratory operations and many institutions in the United States have reported acute staff shortages, we are unaware of any recent studies that provide concrete data detailing workforce needs. In this report, we summarize the results of a technologist-based survey sent to clinical laboratory directors across the United States. Methods: The survey was designed to provide detailed and objective evidence on the current landscape of the technologist workforce in clinical cytogenetics, molecular genetics, and laboratories that have combined both disciplines. Survey questions included demographics, salaries across career stages, retention trends, and hiring requirements and challenges. Results: Analysis of the survey data from 70 US-based submissions showed that cytogenetics laboratories had higher proportion of unfilled technologist positions, whereas molecular laboratories had more applications for each open positions. The technologist retention rate in molecular laboratories was higher than that in cytogenetics. The lack of adequately trained applicants and competitive salary offers by other laboratories were cited as top barriers for filling technologist positions. Conclusion: The results from this survey will serve as normative data in generating solutions to address acute workforce needs in the United States.

The more we learn the more we realize how much there is yet to discover. This is wisdom first articulated by Aristotle and restated by Einstein at a time when physics was awakening to a quantum perspective. As we transition from a genetic to a genomic perspective in medicine, we can be sure that the one thing outpacing our growth in knowledge in our field is an awareness of how much there is yet to discover. This shift from genetics to genomics is not unlike the opening of classical physics into quantum mechanics in that the basic principles we first came to understand through the Mendelian lens are opening into an awareness and attendant uncertainty of an underlying complexity and power only hinted at by classical genetics. As it was true in physics, so it is for our discipline that the earlier and simpler construct continues to do important work for us in channeling knowledge into practical applications. As such, the American College of Medical Genetics and Genomics (ACMG) continues to focus on the use of genetics to improve health. Our efforts include the publication of evidence-based guidelines and secondary findings list, participation in collaborative efforts, such as the Clinical Genome Resource, and providing venues for dissemination, such as meetings and our flagship journal, Genetics in Medicine. As the field expands to embrace the full complexity of the genome and its associated regulatory elements, its derivatives (the methylome, metabolome, and other -omes, including those as yet undiscovered), and its interactions with the environment and other modulators of expression both known and unknown, the ACMG assesses the new discoveries to identify those that have the potential to impact health and translates the data and information from basic science into knowledge (the application of data and information into an understanding of a best clinical practice, as in an evidence-based guideline) and ultimately wisdom (methods to convey knowledge in such a way as to promote the use of knowledge consistently, as in the ACMG ACTion Sheets and Algorithms through the National Coordinating Center to support best practices in newborn screening). Application of this data-information-knowledge-wisdom pyramid to genetics and genomics is at the heart of the activities of the ACMG (Figure 1). While the need for studies that advance our knowledge of genetics and genomics continues to grow even stronger than before, much of what we previously accepted as being beyond our level of agency to meaningfully address, we are beginning to embrace as challenges to be understood and overcome. To take the final steps of knowledge and wisdom, we are now applying tools developed in the field of implementation science that allow us to meaningfully address systems issues that previously would have seemed insuperable barriers to access, care, and cost. There is an emerging science for engaging patients in their own care that enables us to better set goals to achieve truly patient-centered outcomes that seem particularly germane to medical genomics care. In the past, we might have been satisfied with screening and accurate diagnosis, prognosis, and risk, but our current ambitions include therapies and cures for disorders once considered impractical or even hopeless. In terms of setting standards for clinical practice, we are going beyond standards based on expert opinion into the age of systematic evidence reviews and evidence-based guidelines and development of tools to make it easier to apply these guidelines more easily into clinical practice. The changes we are experiencing radiate out beyond the biology of genes and their expression and into the sphere of higher order systems of biology, pharmacology, medicine, health care, and society reminiscent of the perspectives introduced by George Engel in his bio-psycho-social model of medicine back in the 1970s.1Engel G.L. The need for a new medical model: a challenge for biomedicine.Science. 1977; 196: 129-136https://doi.org/10.1126/science.847460Crossref PubMed Scopus (7293) Google Scholar We have come to recognize that disparities in medicine are common and that they propagate along the lines of race, geography, and socioeconomics—some for purely social reasons and others involve an interplay between genes and nonbiological factors. At an earlier stage, we may have accepted such disparities as unfortunate circumstances lying beyond our reach, but there is growing acceptance of the complicity of scientists and practitioners in allowing disparities to emerge and persist. The new ACMG journal, Genetics in Medicine Open (GIM Open) provides a venue to support this expansion in the field. In setting a vision for GIM Open, we commend the Board of the ACMG and an extraordinary editorial board led by Dr Bo Yuan to recognize and articulate not only a rigorous scientific review process but also clear expectations for science that takes stock of the complex systems in which medicine and health care operate and the need for more inclusive scientific design that will engage more diverse populations toward more equitable outcomes across the full range of populations we serve. GIM Open will serve alongside and complement our well-established companion journal, Genetics in Medicine, to advance the highest standards for review publication within the field of medical genetics and genomics and will draw upon wisdom accumulated over many years in setting a bold and ambitious agenda for the best possible open access science in this field. We are calling on esteemed colleagues around the world to help catalyze the success of this new journal by taking to heart the goals and priorities Bo Yuan has articulated in his editorial2Yuan B. Genetics in medicine open to us all.Genet Med Open. 2023; 1 (100772. https://doi.org/10.1016/j.gimo.2023.100772)Google Scholar to submit your best work for publication in GIM Open and to answer the invitation to serve as reviewers to insure the highest levels of peer review. These are exciting times for the field of medical genetics and genomic medicine as we continue our move toward the center of medicine and health care. Thank you to all who are contributing to the success of this journal toward the flourishing of the patients and communities we serve. The authors declare no conflicts of interest.

Neural tube defects (NTDs) and autosomal aneuploidies are major causes of perinatal death and childhood morbidity. Routine screening for these conditions has become a standard part of prenatal care in many countries. Improvements in screening tests for aneuploidy have led to a dramatic shift in the practice patterns. Folate supplementation and screening with maternal serum alpha-fetoprotein followed by comprehensive ultrasound evaluation for screen-positive women has reduced the birth prevalence of NTDs. Continued advances in first and second trimester screening strategies that utilize both serum biochemical and ultrasound evaluation and the introduction of cell-free DNA in maternal serum have dramatically improved prenatal screening performance for chromosomal abnormalities and reduced invasive procedures and iatrogenic complications associated with testing.

(Abstracted from Genet Med 2022;24:509–511) The need for genomic research is a firmly held value of the American College of Medical Genetics and Genomics (ACMG), as this can lead to discovery for the improvement of health outcomes and patient experience. However, an exchange of deidentified genomic data presents a potential opportunity for breach of privacy.

Objective To compile current usage of serum-based prenatal screening for Down syndrome in the United States and compare it with results from a similar 2011/2012 survey. Setting The College of American Pathologists maternal screening proficiency testing survey includes a supplemental question on the first of three yearly distributions. Methods Information regarding tests offered and the monthly number of pregnancies tested for US-based laboratories were reviewed. Results were stratified by size of laboratory, tests offered, and pregnancies tested. Findings were compared to an earlier survey. Results Fifty-six laboratories reported they will have screened 1,131,336 pregnancies in 2020. Of these, 36% are screened by stand-alone first trimester testing, 48% by stand-alone second trimester testing, and 16% using tests that integrate results from both trimesters. Eighty percent of all serum screens were provided by the five laboratories that performed the most screens (at least 50,000). These five performed similar proportions of first or second trimester screens (42.2% and 41.8%, respectively). Compared to eight years earlier, there are now 54% fewer laboratories. Pregnancies screened using the first trimester, second trimester, and integrated protocols were lower by 27%, 69%, and 72%, respectively. The serum screening activity in the US showed a 62% decrease from 2012 levels. During 2012–2020, the number of cell-free DNA tests increased from negligible to 1,492,332. Conclusions Maternal serum screening for common aneuploidies has changed significantly in eight years with fewer laboratories, a shift toward larger laboratories and a 2.5-fold reduction in pregnancies tested, likely due to the introduction of cell-free DNA screening.

PURPOSE:Summarize and interpret results from exercises distributed to laboratories offering cell-free (cf) DNA screening for Down syndrome.METHODS:The College of American Pathologists distributed three patient-derived plasma specimens twice in 2018. Sequencing platforms, test methods, results, and responses to supplemental questions were collected. Results were not graded but discrepancies were identified.RESULTS:Sixty-five laboratories from six continents enrolled; six provided no results. The most common methodology was shotgun/genome sequencing (39/56, 70%). Overall, 40% of the gestational or maternal age responses were incorrect but 45% of the errors were corrected by the next distribution. Fetal fractions from 54 responding laboratories generally agreed with the intended response. No genotyping errors occurred (40/40 for trisomy 21 and 226/226 for euploid challenges) but 10 additional tests failed (3.6%). All 213 fetal sex calls were correct. Participants reported their clinical text for a Down syndrome screen positive test; 39% were classified as inadequate or misleading.CONCLUSION:Patient-derived materials are suitable for all enrolled technologies/methodologies, but collecting material is challenging. Suggested clinical text includes the terms "screen positive" and "screen negative." Overall, laboratories performed well. Future efforts will focus on potential manufactured samples, clarifying results reporting and including additional chromosome abnormalities.

Objective Split-hand/foot malformation (SHFM) is a rare, often debilitating, congenital limb malformation. A single nucleotide polymorphism within the leucine zipper containing kinase AZK ( ZAK ) gene was recently associated with SHFM in two consanguineous Pakistani pedigrees. We hypothesized that additional unrelated patients with the phenotype may carry a pathogenic mutation in ZAK . Methods DNA samples were collected from 38 patients with SHFM and associated hearing loss for Sanger DNA sequencing and in silico analysis. Results Two missense mutations within ZAK were detected in 11 patients, but only one missense variant, p.Ala505Ser, occurred with a presumed rare allele frequency. In silico modeling of the ZAK protein with the p.Ala505Ser substitution indicated a negative binding free energy change (mean ΔΔG = −0.9), representing destabilization of the ZAK tertiary structure. Additional laboratory analysis demonstrated a chromosome region 7q21.3-q22.1 deletion. This locus contains the SHFM-1 causative genes SHFM1 , DLX5 , and DLX6 (distal-less homeobox-5 and -6). Conclusions We report a novel and rare missense variant, ZAK p.Ala505Ser, in one patient with SHFM from a non-consanguineous pedigree. This variant mildly destabilizes the ZAK tertiary structure. Although this mutation involved a deletion at the SHFM1 locus (7q21.3-q22.1), ZAK signaling destabilization may have contributed to the phenotype, which included hearing loss.

Department of Pathology and Laboratory Medicine, Women & Infants Hospital and the Alpert Medical School at Brown University, Providence, Rhode Island Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China Victorian Clinical Genetics Services (VCGS), Murdoch Children's Research Institute, Melbourne, Victoria, Australia Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Prenatal Genetic Diagnosis Unit, Genetic Institute, Tel Aviv Medical Center, Faculty of Medicine Tel Aviv University, Tel Aviv, Israel Department of Human Genetics, KU Leuven, Leuven, Belgium Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina University of South Carolina SOM Greenville, Greenville, South Carolina Division of Maternal Fetal Medicine and Reproductive Genetics, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts

To the Editor: We appreciate the opportunity to respond to the comments of Knoppers and colleagues1.Knoppers BM, et al. Letter: Relearning the 3 R’s: reinterpretation, Recontact, and Return of Genetic VariantsGoogle Scholar regarding the American College of Medical Genetics and Genomics (ACMG) statement, “Patient re-contact after revision of genomic test results: points to consider,”2.David KL, Best RG, Brenman LM, ACMG Social Ethical Legal Issues Committee, et al. Patient re-contact after revision of genomic test results: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 22 Dec 2018; https://doi.org/10.1038/s41436-018-0391-z [Epub ahead of print].Google Scholar recently e-published before print in Genetics in Medicine. The comments in Knoppers’ letter, however, reflect a misunderstanding of our document and conflate the clinical and research settings. We reiterate that the ACMG statement reflects practice oF.A.merican clinical geneticists who provide direct patient services. It does not speak to the research setting. Current American clinical and legal standards and fundamental ethical principles inform our Points to Consider. We clearly state that reasonable efforts should be made by providers (not necessarily only physicians) to contact the patient (Points to Consider #8). These efforts may encounter “resource constraints” that may be similar or dissimilar to those in the research setting. The letter of Knoppers et al. points out that the American Society of Human Genetics draft position3.Levy HP. Duty to re-contact in the research environment; the ASHG draft position statement presented ASHG Annual Meeting, San Diego, October 19, 2018.Google Scholar limits researchers’ “duty to re-contact” to the duration of the project funding. On the other hand, clinicians’ concerns that patients be properly informed of revised interpretation may extend indefinitely after the original consultation. Given the practicalities of contacting patients potentially years after the results oF.A. genetic test were first reported, it is neither reasonable nor realistic to promise more than providers can deliver. Despite best efforts on the part of laboratories and clinicians, re-contact cannot be guaranteed unless the patient initiates the process. The ACMG statement does not place sole responsibility for re-contact on anyone; rather the statement stresses a collaborative approach. As highlighted in our Points to Consider, the ACMG recognizes that its position may well evolve with developments in molecular technology and variant interpretation, electronic record and communication technology, and the legal environment. Therefore, the ACMG Points to Consider is meant as the best approach on these difficult issues in the current context of clinical care. The authors declare no conflicts of interest. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Purpose Noninvasive prenatal screening (NIPS) for fetal aneuploidy via cell-free DNA has been commercially available in the United States since 2011. In 2016, the American College of Medical Genetics and Genomics (ACMG) issued a position statement with specific recommendations for testing laboratories. We sought to evaluate adherence to these recommendations. Methods We focused on commercial laboratories performing NIPS testing in the United States as of 1 January 2018. Sample laboratory reports and other materials were scored for compliance with ACMG recommendations. Variables scored for common and sex chromosome aneuploidy detection included detection rate, specificity, positive and negative predictive value, and fetal fraction. Labs that performed analysis of copy-number variants and results for aneuploidies other than those commonly reported were identified. Available patient education materials were similarly evaluated. Results Nine of 10 companies reported fetal fraction in their reports, and 8 of 10 did not offer screening for autosomal aneuploidies beyond trisomy 13, 18, and 21. There was inconsistency in the application and reporting of other measures recommended by ACMG. Conclusions Laboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.

To the Editor: We appreciate the interest by Myriad Women’s Health in our recent study on the adherence by commercial companies to the American College of Medical Genetics and Genomics (ACMG) recommendations on cell-free DNA (cfDNA) noninvasive prenatal screens (NIPS).1.Taber J. Inaccuracies and shortcomings in “Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations”. Genet Med. 2019. https://doi.org/10.1038/s41436-019-0555-5.Google Scholar,2.Skotko BG, et al. Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations. Genet Med. 2019. https://doi.org/10.1038/s41436-019-0485-2 [Epub ahead of print].Google Scholar We are eager to update our assessments with any new information, and we welcome direct contact and dialogue from NIPS companies. Indeed, we have already received revised materials from at least one lab. As indicated in our paper, the latest version of Table 2 from our study is posted at https://prenatalinformation.org/table/, reflective of any new supporting documentation that has been received from NIPS companies. The documentation we used for our analyses is itemized in the Supplementary Materials to our paper. For Counsyl’s Prelude (now Myriad’s Prequel) NIPS test, this included analyzing patient and provider material posted on their web page and provided at their exhibitors' booth during the 2018 ACMG meeting. We also analyzed sample reports provided directly to us from Counsyl. (To be objective and consistent in our methodology, we directly reached out to all of the NIPS laboratories to obtain any missing sample reports that could not be found on their web pages.) To be ecologically valid, we sought to mimic information requests from ordering physicians and/or expectant parents. After much discussion, we chose to analyze those companies that had the largest market share of the NIPS tests commercially available in the United States as of 1 January 2018. We agree that NIPS tests from single health systems, single-hospital systems, and academic/university settings should also be analyzed, and we hope to do so in future research. We also agree that additional studies should examine why laboratories are not following certain ACMG recommendations. The authors noted three primary concerns. First, we applaud their efforts in including detection rate (DR), specificity (SPEC), positive predictive value (PPV) (patient-specific), and negative predictive value (NPV) for common aneuploidies on their test reports. We chose to give Counsyl a yellow (or partial adherence) to recommendation 1 because not all pretest marketing materials had the same consistent information. We sought to be as objective as possible, simply looking for adherence to the ACMG recommendations as they were written. For recommendation 8, we gave Counsyl a red (or little to no adherence) because Counsyl wrote on sample reports for some sex aneuploidies that “PPV… cannot be calculated due to insufficient prevalence data.” The ACMG guidelines recommend that “[l]aboratories provide modeled PPV when reporting positive results for which neither patient-specific nor population-derived PPV are possible.”3.Gregg A.R. et al.Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.1:CAS:528:DC%2BC28Xhs1aks77L10.1038/gim.2016.97Genet Med. 2016; 18: 1056-1065Google Scholar Second, the authors state that they “do not believe it is clinically practical or responsible” to include the data requested by ACMG in recommendation 7. The ACMG position statement allows the use of modeled data when laboratory-specific data are not available.3.Gregg A.R. et al.Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.1:CAS:528:DC%2BC28Xhs1aks77L10.1038/gim.2016.97Genet Med. 2016; 18: 1056-1065Google Scholar The statement further says that “when laboratories cannot report specific DR, SPEC, PPV, and NPV, screening for those CNVs should not be performed by that laboratory.”3.Gregg A.R. et al.Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.1:CAS:528:DC%2BC28Xhs1aks77L10.1038/gim.2016.97Genet Med. 2016; 18: 1056-1065Google Scholar We appreciate that these authors did not have disagreement with our assessment, per se, but rather with this ACMG recommendation in general. We defer to the ACMG on when their position statement on NIPS might be updated again. Third, we acknowledge the good faith efforts by Myriad to provide information about patient resources in their test reports. When assessing the provision of patient education resources, we constructed a matrix of the five recommended patient education resources and the five provider resources mentioned in the ACMG guidelines.3.Gregg A.R. et al.Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.1:CAS:528:DC%2BC28Xhs1aks77L10.1038/gim.2016.97Genet Med. 2016; 18: 1056-1065Google Scholar If a lab listed any of one of these resources on their lab reports or publicly available websites or patient education pamphlets, then we assigned a yellow rating for making a good faith effort. A red rating meant the labs provided none of the recommended resources in any publicly available medium or lab reports. A company was rated a green score if they listed at least 3 of 5 recommended patient and provider resources. Myriad did offer one of the recommended patient education resources in multiple mediums, as well as references to additional valuable educational resources beyond the recommendations, but they were missing all the recommended provider resources. The responsible clinical implementation of cfDNA NIPS tests requires cooperation and collaboration from labs, clinicians, insurers, professional societies, and patients alike. Commercial labs are vital partners who have a direct impact on every patient undergoing testing. They also remain the greatest source of funding for materials to support those patients. Through adherence to the ACMG recommendations, we hope that labs will help ensure that providers are getting all the information they need about testing and that vulnerable families are not left isolated and confused about powerful genetic information. The conflicts for the authors remain unchanged from those declared in our original publication. Financial conflicts of interest: B.G.S. occasionally consults on the topic of Down syndrome (DS) through Gerson Lehrman Group. He receives remuneration from DS nonprofit organizations for speaking engagements and associated travel expenses. B.G.S. receives annual royalties from Woodbine House, Inc., for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters. Within the past 2 years, B.G.S. has received research funding from F. Hoffmann–La Roche, Inc. to conduct clinical trials on study drugs for people with DS. B.G.S. is occasionally asked to serve as an expert witness for legal cases where DS is discussed. M.W.L. and S.M. are employees of the National Center for Prenatal & Postnatal Resources at the University of Kentucky, which produces and sells patient educational material recommended by professional guidelines; M.W.L. and S.M. receive no direct compensation from the sale of such materials. K.B. has financial holdings in GenomeSmart, a patient education platform. M.A.A. is an employee of Mayo Clinic, which provides cell-free DNA testing services through Mayo Medical Laboratories; M.A.A. receives no direct compensation from the sale of such tests. Other conflicts of interest: Beyond the items mentioned in the financial disclosures above, B.G.S. serves in a nonpaid capacity on the Honorary Board of Directors for the Massachusetts Down Syndrome Congress, the Board of Directors for the Band of Angels Foundation, and the Professional Advisory Committee for the National Center for Prenatal and Postnatal Down Syndrome Resources. B.G.S. has a sister with DS. M.W.L. serves in a nonpaid capacity on the D.S. Education Foundation for Down Syndrome of Louisville. M.W.L. has a daughter with DS. S.M. has a son with DS. M.A.A. has received travel funding compensation from the Association for X and Y Chromosome Variations. The other authors declare no conflicts of interest. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open neural tube defects (ONTDs) include open spina bifida (OSB) and anencephaly. These defects are caused by incomplete closure of the neural tube at about 4 weeks of pregnancy. Levels of early second-trimester maternal serum (ms) alpha-fetoprotein (AFP) are sufficiently elevated in affected pregnancies to be used as a population-based screening test. The basic screening methodology was described in the late 1970s and screening programs were active a few years later. By identifying pregnancies with the highest msAFP levels, about 80% of OSB and 95% of anencephaly can be identified as early as 16 weeks gestation. The interpretation of msAFP levels is complicated by the need to consider multiple factors such as gestational age, maternal weight, maternal race, multiple gestations, and more. Testing for AFP and acetylcholinesterase in amniotic fluid and/or identification of the lesion by targeted ultrasound is considered diagnostic of ONTD. When a diagnosis is made, options include termination, surgery after delivery, or in utero surgery, depending on factors such as location and size of the defect, and the presence of any additional anomalies. Screening for ONTD should be performed as part of a comprehensive program linking primary obstetrical care providers, laboratorians, and high-risk clinicians.

Changes in interpretation of complex clinical genomic test results are inevitable. Ultimately, the ordering health-care provider, clinical geneticist, clinical laboratory, referring specialty and primary care physician, patient, and family each may have a role regarding re-contact. These expectations should be explicitly delineated as part of the informed consent process before the sample is obtained and reviewed again when disclosing initial results.

DISCLAIMER:This statement is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Noninvasive prenatal screening using cell-free DNA (NIPS) has been rapidly integrated into prenatal care since the initial American College of Medical Genetics and Genomics (ACMG) statement in 2013. New evidence strongly suggests that NIPS can replace conventional screening for Patau, Edwards, and Down syndromes across the maternal age spectrum, for a continuum of gestational age beginning at 9-10 weeks, and for patients who are not significantly obese. This statement sets forth a new framework for NIPS that is supported by information from validation and clinical utility studies. Pretest counseling for NIPS remains crucial; however, it needs to go beyond discussions of Patau, Edwards, and Down syndromes. The use of NIPS to include sex chromosome aneuploidy screening and screening for selected copy-number variants (CNVs) is becoming commonplace because there are no other screening options to identify these conditions. Providers should have a more thorough understanding of patient preferences and be able to educate about the current drawbacks of NIPS across the prenatal screening spectrum. Laboratories are encouraged to meet the needs of providers and their patients by delivering meaningful screening reports and to engage in education. With health-care-provider guidance, the patient should be able to make an educated decision about the current use of NIPS and the ramifications of a positive, negative, or no-call result.Genet Med 18 10, 1056-1065.

Purpose: We sought to determine whether tests for fetal aneuploidy based on next-generation sequencing of cell-free DNA in maternal circulation have had an impact on routine serum-based screening in the general pregnant population. Methods: We compared results from laboratory surveys in 2011 and 2014 that reported types of prenatal serum screening tests and numbers of tests performed. Testing records from two prenatal serum screening laboratories examined temporal trends in the proportion of screened women 35 years of age and older from 2008 (or 2009) to 2014. Results: The 82 laboratory survey results available for comparison showed that 1.7 million women were screened in 2014, a 5% increase over 2011. In the two screening laboratories, the proportion of screened women age 35 and older increased for several years but then experienced reductions of 8 and 18% by mid-2014 when compared with the highest rates observed. Conclusion: As of 2014, maternal plasma DNA testing appears to have had only a minor impact on serum screening rates in the United States. Ongoing surveillance has the potential to determine if, and when, DNA testing begins to replace serum testing as a primary screen for Down syndrome in the United States. Genet Med 17 11, 897–900.

Hypertension or an elevated blood pressure continues to be a major risk factor for cardiovascular disease. Despite intensive public education including lifestyle modification programs and the availability of safe and effective pharmacologic agents to treat hypertension, the treatment and control of hypertension is suboptimal. Over the past several decades, there have been tremendous advances in the use of genetics to prevent, detect, and treat human disease states. Despite these advances and an intensive effort, the application of genetics to the broad population with hypertension has not met expectations. This review will address our present understanding and use of genetics in hypertension and areas where genetics may impact significantly our approach and clinical treatment of hypertension in the future.

The genetic testing and genetic screening of children are commonplace. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. The growing literature on the psychosocial and clinical effects of such testing and screening can help inform best practices. This policy statement represents recommendations developed collaboratively by the American Academy of Pediatrics and the American College of Medical Genetics and Genomics with respect to many of the scenarios in which genetic testing and screening can occur.