Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: This workgroup aimed to develop an evidence-based clinical practice guideline for the use of noninvasive prenatal screening (NIPS) for pregnant individuals at general risk for fetal trisomy 21, trisomy 18, or trisomy 13 and to evaluate the utility of NIPS for other chromosomal disorders. METHODS: The NIPS Evidence-Based Guideline Work Group (n = 7) relied on the results from the recent American College of Medical Genetics and Genomics (ACMG) systematic review to form the evidentiary basis of this guideline. Workgroup members used the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework to draft recommendations. The guideline underwent extensive internal and external peer review with a public comment period before approval by the ACMG Board of Directors. RESULTS: Evidence consistently demonstrated improved accuracy of NIPS compared with traditional screening methods for trisomies 21, 18, and 13 in singleton and twin gestations. Identification of rare autosomal trisomies and other microdeletion syndromes with NIPS is an emerging area of interest. CONCLUSION: ACMG strongly recommends NIPS over traditional screening methods for all pregnant patients with singleton and twin gestations for fetal trisomies 21, 18, and 13 and strongly recommends NIPS be offered to patients to screen for fetal sex chromosome aneuploidy.

Prenatal serum screening for Down syndrome and neural tube defects in the United States: Changes in utilization patterns from 2012 to 2020.

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.

Laboratory screening and diagnosis of open neural tube defects, 2019 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

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.

Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations.

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.

Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.

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.

Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States?

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.

Screening for down syndrome in the United States: results of surveys in 2011 and 2012.

CONTEXT: Participants in a College of American Pathologists external proficiency testing program for first and second trimester Down syndrome screening. OBJECTIVES: To determine the number of women screened for Down syndrome in the United States, along with the type of test received and to compare those results to earlier surveys in 1988 and 1992. DESIGN: Questionnaires regarding the type and number of Down syndrome tests performed per month were completed by participants in early 2011 and again in early 2012. RESULTS: After accounting for some of the missing responses, data from up to 131 laboratories indicated that 67% (2 764 020 of 4 130 000) to 72% (2012: 2 963 592 of 4 130 000) of US pregnancies received prenatal screening for Down syndrome. Second trimester tests were most common (2012: 60%; 1 770 024 of 2 963 592), followed by integrated (2012: 21%; 627 876 of 2 963 592), and first trimester (2012: 19%; 565 692 of 2 963 592). The 6 largest laboratories tested 61% of screened pregnancies and offered the widest array of tests, while the smallest 32 tested 1% and almost always offered only second trimester tests. CONCLUSIONS: The current population estimate of 72% pregnancies screened annually is higher than estimates from 1988 (25%) and 1992 (50%). Available testing choices are also more varied, and all testing methods perform better than those methods available 10 years ago. Clinicians should ensure that women are offered tests that follow recommended best-practice testing protocols, and screening laboratories should assess whether patient needs are being met.

Maternal obesity, folate intake, and neural tube defects in offspring.

BACKGROUND: We investigated the association between maternal obesity (body mass index [BMI] ≥ 30) and the risk of a neural tube defect affected pregnancy (NTD). We also studied relationships between perinatal folate intake from food and the NTD risk by maternal BMI. METHODS: Data came from a state-wide case-control study conducted between 1992 and 1997 in South Carolina including 179 women with NTD-affected pregnancies and 288 women without NTD-affected births. A majority of case mothers (77%) and controls (86%) were interviewed within 6 months after delivery or pregnancy termination. Logistic regression models were used to examine the association between maternal obesity and the NTD risk after adjusting for maternal race, age, education, smoking, alcohol/drug use, chronic conditions, and multivitamin use within six periconceptional months. Stratified analysis by maternal BMI (≥25 vs. <25) was conducted for the association between food folate and the NTD risk. RESULTS: After adjustment for confounders, obese women (BMI ≥ 30) had twice higher odds of having an NTD-affected pregnancy (odds ratios [OR] = 2.06, 95% confidence interval [CI] = 1.12, 3.81) than normal weight women (BMI: 18.0-24.9). Compared to the lowest quartile of average daily folate intake from food, the upper three quartiles had lower odds of NTDs in offspring. The NTD-protective association was stronger in overweight/obese women (BMI ≥ 25) than in normal/underweight women (BMI < 25). CONCLUSIONS: These results support previous studies suggesting maternal obesity as a risk factor for NTDs. Higher intakes of dietary folate were associated with decreased NTD risk that was stronger in overweight and obese women.

Balanced information about Down syndrome: what is essential?

The purpose of this study was to explore the perspectives of genetic counselors and parents of children with Down syndrome to define essential information for the initial discussion of a new diagnosis. We compared information given in both prenatal and postnatal settings, and also aimed to distinguish differences between the informational needs of parents and the information genetic counselors provide. Online surveys were distributed to members of the National Down Syndrome Congress, National Down Syndrome Society, and National Society of Genetic Counselors. Participants included 993 parents of children with Down syndrome and 389 genetic counselors. Participants rated 100 informational features about Down syndrome as Essential, Important, or Not Too Important for inclusion in the first discussion of the diagnosis. Responses identified 34 essential informational items for the initial discussion of Down syndrome, including clinical features, developmental abilities, a range of prognostications, and informational resources. Healthcare providers should consider incorporating these items in their initial discussion of a diagnosis in both prenatal and postnatal settings. Statistically significant differences between parent and genetic counselor responses illustrate that information is valued differently and that parents appreciate information about the abilities and potential of people with Down syndrome, as opposed to clinical details. Balancing clinical information with other aspects of the condition, as well as a better understanding of the information parents consider most important, may enable healthcare professionals to more effectively satisfy families' informational needs following a new diagnosis of Down syndrome.

Long term maintenance of neural tube defects prevention in a high prevalence state.

OBJECTIVE: To assess the efficacy of folic acid (FA) supplementation and fortification in preventing neural tube defects (NTDs) in a high prevalence region of the United States. STUDY DESIGN: Active and passive surveillance methods were used to identify all fetuses/infants affected with an NTD in South Carolina. Prevalence rates were compared with FA intake to determine the effects of increased intake on NTD occurrence and recurrence. RESULTS: From 1992 to 2009, 916 NTD cases occurred in South Carolina, with isolated defects comprising 79% of cases. The NTD rate decreased 58% during this period. There was one NTD-affected pregnancy in 418 subsequent pregnancies (0.2%) in mothers with earlier NTD-affected pregnancies who consumed periconceptional FA supplements, and there were 4 NTDs in 66 pregnancies (6.1%) in which the mother did not take FA supplements. FA supplementation increased from 8% to 35% from 1992 to 2007, and knowledge of the protective benefits of FA increased from 8% to 65% in women of childbearing age. CONCLUSIONS: Increased periconceptional intake of FA appeared to reduce NTDs in a high-prevalence region. The rate of spina bifida and anencephaly in South Carolina is now essentially the same (0.69 cases per 1000 live births and fetal deaths) as the 1998 to 2005 US rate (0.69).

Constitutional mosaic trisomy 21 and azoospermia: a case report.

Constitutional full trisomy 21 is a common disorder in which abnormal spermatogenesis has been previously described. However, constitutional mosaic trisomy 21 in an otherwise normal but infertile male has not been explored. We report a case with low level mosaic trisomy 21 in a non-syndrome but azoospermic patient. We also propose that the patient's azoospermia may be related to the constitutional mosaic trisomy 21 and thus resulting in a late onset of testicular failure.

Genetic red flags: clues to thinking genetically in primary care practice.

This article presents an approach to "thinking genetically" in primary care. Busy practitioners often lack the time to consider thoroughly whether their patients have an underlying genetic diagnosis. To assist the primary care clinician, a working group of the Genetics in Primary Care Faculty Development Initiative developed a simple mnemonic, Family GENES, that alerts the clinician to consider genetic causes in the differential diagnosis. In addition to family history, the red flags include Groups of anomalies, Early or Extreme presentations of common diseases, Neurodevelopmental or Neurodegenerative conditions, Exceptional or unusual pathology, and Surprising laboratory values. This article discusses the components of the mnemonic, provides examples, and gives guidelines to appropriate actions once the possibility of a genetic diagnosis has been raised.

Trisomy 16 in a pigtailed macaque (M. nemestrina) with multiple anomalies and developmental delays.

A female pigtailed macaque (Macaca nemestrina) with unusual physical characteristics, deficits in learning and cognitive tasks, abnormal social behavior, and abnormal reflexes and motor control was followed from birth until 3 years of age and found to have trisomy 16, which is homologous to trisomy 13 in humans. The animal described here showed similar features to cases of trisomy 16 and 18 (human trisomy 13 and 18, respectively) reported previously in nonhuman primates. However, both significant differences and similarities were found when compared with the homologous human trisomy. Evaluation of the genetic components of these disorders as well as systematic developmental evaluation can lead to new insights into the genetic basis of speciation, development, and the underlying differences between humans and their closest living relatives.