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ispartof: PRENATAL DIAGNOSIS vol:41 issue:10 pages:1222-1232 ispartof: location:England status: published

Summarize and interpret results from exercises distributed to laboratories offering cell-free (cf) DNA screening for Down syndrome. 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. 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. 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.

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.

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.

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. 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. 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. Laboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.

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.

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.

Up to three-quarters of pregnant women in the USA receive prenatal screening for Down syndrome (DS) and other fetal disorders. Historically, such testing has been based on combinations of maternal age, biochemical markers, and ultrasound findings with maximal detection rate for Down syndrome of 90% (sensitivity) at a false-positive rate of 2% (1-specificity) in a general pregnancy population. In 1997, a group from Hong Kong identified “fetal” cell-free (cf)DNA in maternal circulation. Unlike serum screening, cfDNA screening for Down syndrome is based directly on detection of extra chromosome 21 material from the fetal/placental unit. Following the 2011 publication of a prospective clinical trial of cfDNA, the first commercial prenatal screening test for Down syndrome based on circulating cfDNA was introduced into clinical practice. Among over 2000 DS and 200,000 euploid samples successfully tested, the detection rate for Down syndrome by a variety of cfDNA methods is presently over 99%, with a false-positive rate of about 0.2%. Multiple methodologies introduced by different laboratories have also shown detection rates at or above 95% for both trisomy 18 and trisomy 13. Occasionally (

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. 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. 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. 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.

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 testing standards. The analysis of cell-free fetal DNA in maternal circulation for fetal aneuploidy screening is likely the first of major steps toward the eventual application of whole fetal genome/whole fetal exome sequencing. Genet Med advance online publication 00 Month 2013

A mixture measurement error model built upon skew normal distributions and normal distributions is developed to evaluate various impacts of measurement errors to parameter inferences in logistic regressions. Data generated from survey questionnaires are usually error contaminated. We consider two types of errors: person-specific bias and random errors. Person-specific bias is modelled using skew normal distribution, and the distribution of random errors is described by a normal distribution. Intensive simulations are conducted to evaluate the contribution of each component in the mixture to outcomes of interest. The proposed method is then applied to a questionnaire data set generated from a neural tube defect study. Simulation results and real data application indicate that ignoring measurement errors or misspecifying measurement error components can both produce misleading results, especially when measurement errors are actually skew distributed. The inferred parameters can be attenuated or inflated dep...

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.

Growing use of remote sensing in scientific and forensic analysis requires collecting large quantities of signature data from a variety of sensors requiring various techniques as well as careful consideration of environmental conditions. The quantity of collected signature data continues to grow rapidly and the challenge of storing, classifying, searching and exchanging of signatures has significantly increased. For example, the Joint Improvised Explosive Device Defeat Organization (JIEDDO) Integrated Signatures Program (ISP) has collected approximately one million IR, Raman, Mass Spec, RF and other signatures that must be effectively managed. This paper discusses approaches for standardizing metadata across different phenomenology, data interchange formats, unique identification of signatures, signature quality metrics, facilitating third party analysis tools and large signature library management and distribution. Each of these items must be considered when developing a standard for collected signatures.

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.

This case represents an example of an unusual T-cell lymphoblastic leukemia/lymphoma syndrome associated with eosinophilia and myeloid malignancy in a young boy. This case is one of only five reported "leukemic" variants of the disease and demonstrates the importance of considering this poor prognostic diagnosis in pediatric acute lymphoblastic leukemia. This case also illustrates the importance of an interactive multidisciplinary approach to the laboratory evaluation of a leukemia patient.

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.

Studies have established that daily folate supplements in the periconceptional period lower the risk of both first and recurrent neural tube defects (NTDs). There also are indications that dietary folate is effective, butthis is less definite than is the case for supplementation. This population-based case-control study, carried out in 1992 to 1997, enrolled 179 women having NTD-affected pregnancies and 288 randomly chosen control women. They completed a food frequency questionnaire, and also were interviewed in person about their reproductive history, lifestyle, and multivitamin use. The interval of interest extended from 3 months before conception through the first trimester. Nearly 60% of affected pregnancies were terminated electively. A large majority of NTDs were spina bifida or anencephaly. The case and control groups were comparable demographically and behaviorally except that more case women were white and had been exposed to cigarette smoke. Barring inconsistent users, 68.8% of case women and 90.7% of control subjects took multivitamins, including folic acid, on a daily basis. Fewer than 10% of women in either group had low dietary folate intake and also did not use multivitamins. After adjusting for age, race, body mass index, smoke exposure, and the use of multivitamin folic acid, a protective effect was evident only in the highest quartile of dietary folate; the odds ratio (OR) was 0.4. Using 0.4 mg or more of multivitamin folic acid at least 3 times a week did not significantly lower the risk of an NTD (adjusted OR, 0.55). The OR for NTDs in the top quartile of combined dietary folate and daily multivitamin folic acid (total folate) was 0.35 (95% confidence interval, 0.17-0.72). This translates into a 65% reduction in risk. The OR figures for the other quartiles of total folate, although not statistically significant, were in the expected direction. There was a trend toward increasing use of multivitamin folic acid over the 5-year study period. Further studies in large populations are needed to be sure that current food fortification practices and multivitamin supplementation will in fact raise folate levels to the point where most NTDs are prevented without adverse effects.

Twelve spontaneous ovarian tumors were found in the Southwest Foundation for Biomedical Research baboon colony. These included four granulosa cell tumors, three teratomas, two endometrioid carcinomas, one seromucinous cystadenofibroma, a cystic papillary adenocarcinoma, and an ovarian carcinoma. Age was a pre-disposing factor. With one exception, the tumors of surface epithelial- and sex cord-stromal origin occurred in baboons over 17 years of age. The exceptional animal was 7 years of age when a malignant granulosa cell tumor with Sertoli cell differentiation was identified. The two endometrioid tumors, which were found in 17- and 30-year-old animals, were both associated with endometriosis. In contrast, the teratomas, which are tumors of germ cell origin, were found in younger animals, i.e. 17 years of age or younger. One case of an ovarian carcinoma with metastases was observed in a 6-month-old infant. Cases of spontaneous ovarian tumors from the literature are reviewed.

Objective: With the use of microsatellite analysis, we sought to determine the incidence of maternal cell contamination in 46,XX products of conception consisting of villi or a combination of villi and membranous material. Study Design: Deoxyribonucleic acid from cultured fibroblasts of 46,XX products of conception specimens and a corresponding maternal blood sample were obtained from 31 women. Maternal and fetal genotypes for several highly polymorphic microsatellite markers were compared. Results: Maternal cell contamination was present in 26 (89.7%) of the 29 products of conception specimens from which conclusive results were obtained. The contamination appeared to completely obscure the fetal material in 24 of these specimens. Conclusions: A significant proportion of 46,XX karyotypes from products of conception represents maternal cell contamination. When maternal cells rather than fetal cells are karyotyped, no information is gained regarding the chromosome constitution of the abortus, and genetic counseling regarding recurrence risks for future pregnancies may be inaccurate. Thus laboratories should exercise caution when reporting normal female karyotypes on products of conception and should consider using microsatellite analysis to determine whether 46,XX results are truly representative of the fetal karyotype. (Am J Obstet Gynecol 2001;185:198-203.)

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.

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.

New technologies available in the field of medical genetics have increased the importance of responsible ethical decision-making among genetic counselors. A 1985 national survey of M.D. and Ph.D. genetic counselors assessed ethical attitudes using case scenarios designed to simulate dilemmas faced in genetic counseling (Wertz and Fletcher, 1988b). The current study focuses on attitudes of M.S. genetic counselors using similar scenarios, allowing for effective comparisons. M.S. counselors were more willing than M.D. and Ph.D. counselors to maintain patient confidentiality when screening for Huntington's Disease and occupational diseases, and a greater number would agree to counsel patients pursuing prenatal testing for sex selection. A majority of M.S. counselors would disclose an XY karyotype to a phenotypically female patient. M.S. counselors reasoned that respect for patient autonomy and patient confidentiality justified their decisions in many cases. The importance of these principles is discussed and questioned.

One hundred and thirty-six individuals with a family history of X-linked adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN) were given a questionnaire surveying their sociodemographic characteristics, knowledge of X-linked inheritance, and attitudes toward prenatal, presymptomatic, and carrier testing. Of the respondents, 68% indicated that they would use prenatal testing. Of these, 57.1% would terminate a pregnancy of a male fetus hemizygous for the ALD gene and 13.5% would reportedly choose to terminate a heterozygote female fetus. Presymptomatic testing would be used by 88.7% of respondents to test at-risk sons and carrier testing would reportedly be used by 95.4% of respondents to test their at-risk daughters. Respondents correctly answered an average of 61% of the questions testing understanding of X-linked inheritance. This indicates a strong interest in prenatal, presymptomatic, and carrier testing and a need for genetic counselors to provide information about these available tests and X-linked inheritance.

As part of a multicenter prospective study, second-trimester human chorionic gonadotropin and alpha-fetoprotein concentrations were evaluated. Data included maternal age, human chorionic gonadotropin level, alpha-fetoprotein level, weight, race, and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases, that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women, and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes, 54 (21.2%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median and 26 (10.2%) had alpha-fetoprotein levels greater than 2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy, 6 (54.5%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome, weight and race adjustments are necessary for accurate risk assessment.

Many believe that nanotechnology will be disruptive to our society. Presumably, this means that some people and even whole industries will be undermined by technological developments that nanoscience makes possible. This, in turn, implies that we should anticipate potential workforce disruptions, mitigate in advance social problems likely to arise, and work to fairly distribute the future benefits of nanotechnology. This general, somewhat vague sense of disruption, is very difficult to specify – what will it entail? And how can we responsibly anticipate and mitigate any problems? We can't even clearly state what the problems are anticipated to be. In fact, when we move from sweeping policy statements to more concrete accounts, nanotechnology seems to bifurcate into two divergent streams: one is fairly continuous with current developments, extending extant science in a quantitative way; the other is radically new, and includes science fiction-like dreams of molecular manufacturing and assemblers, with their utopian (or dystopian) scenarios of absolute plenty (or runaway self-replication). In these cases, “disruption” takes on the valence of Huxley's brave new world.

Objective To evaluate the incidence of chromosomal abnormalities in ectopic pregnancy chorionic villi. Methods A prospective study of patients with the diagnosis of ectopic pregnancy was conducted, with chorionic villi obtained at the time of surgical therapy cultured and analyzed for karyotype. Review of the patient's medical record and ultrasound evaluation was then completed and findings correlated with karyotype results. Results Twenty-two patients undergoing surgery for the diagnosis of ectopic pregnancy yielded chorionic villi for culture. Successful culture was performed in 21 patients, with 3 (14%) revealing abnormal karyotypes. Review of the medical record showed ultrasound results consistent with fetal development or a gestational sac in 15 of 18 patients with normal chromosomal analysis. Three of 6 patients without fetal development yielded abnormal chromosomal findings. Conclusion Our results confirm that a high degree of success can be achieved in the karyotype analysis of ectopic pregnancy chorionic villi and that these conceptuses have a rate of abnormality similar to that reported for intrauterine gestations. Our data further suggest that when a gestational sac or fetal pole is identified by ultrasound, there is usually a normal karyotype.

Graft rejection following bone marrow transplantation is more common in patients who receive their grafts from alternative donors and whose marrow is T cell depleted. Rejection in these patients is mediated by persistent host cells that interfere with successful establishment of donor-derived hematopoietic recovery. We describe a patient with chronic myelogenous leukemia in accelerated phase who rejected a T cell-depleted bone marrow graft, 2 months following partially mismatched related donor bone marrow transplant. Unmanipulated peripheral blood donor leukocyte infusion, without additional chemotherapy or immunosuppressive therapy resulted in complete hematopoietic recovery. Cytogenetics and RFLP demonstrated hematopoietic donor chimerism. The patient did not develop graft-versus-host disease.

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.

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.

Twelve spontaneous ovarian tumors were found in the Southwest Foundation for Biomedical Research baboon colony. These included four granulosa cell tumors, three teratomas, two endometrioid carcinomas, one seromucinous cystadenofibroma, a cystic papillary adenocarcinoma, and an ovarian carcinoma. Age was a pre-disposing factor. With one exception, the tumors of surface epithelial- and sex cordstromal origin occurred in baboons over 17 years of age. The exceptional animal was 7 years of age when a malignant granulosa cell tumor with Sertoli cell differentiation was identified. The two endometrioid tumors, which were found in 17- and 30-year-old animals, were both associated with endometriosis. In contrast, the teratomas, which are tumors of germ cell origin, were found in younger animals, i.e. 17 years of age or younger. One case of an ovarian carcinoma with metastases was observed in a 6-month-old infant. Cases of spontaneous ovarian tumors from the literature are reviewed.

Objective To investigate presence of trisomy in amniotic epithelium (uncultured amnion) and mesenchyme (cultured amnion) from mosaic cases to understand the origins of these tissues and their relationship to pregnancy outcome. Methods Polymerase chain reaction (PCR) of microsatellite loci was used to determine the presence of trisomy (of meiotic origin only) in amnion samples from 33 placentas previously ascertained because of a prenatal diagnosis of trisomy mosaicism that was predominantly confined to the placental tissues. Results In 16 (48%) of 33 cases, trisomy was confirmed to be present by molecular analysis of uncultured amnion. In contrast, cytogenetic analysis of cultured amnion showed trisomy in only 2 of 20 informative cases. The molecular detection of trisomy in amnion was strongly associated with poor pregnancy outcome (intrauterine growth restriction, fetal anomalies and/or intrauterine/neonatal death) even when analysis was limited to cases negative for the trisomy on amniotic fluid (N = 22, p = 0.0005). Conclusions We infer that amniotic mesenchyme (usually diploid) derives from early embryonic mesoderm of the primitive streak and not from the hypoblast as is commonly cited. Trisomy in amniotic epithelium suggests that high numbers of abnormal cells were present in the epiblast, and this correlates with poor outcome even when the subsequently derived fetus and amniotic mesenchyme appear to carry only diploid cells. Copyright © 2002 John Wiley & Sons, Ltd.

Purpose: Folate insufficiency due to nutritional deficiency or folate processing gene mutations has been proposed as a trisomy 21 risk factor. This study examined the possibility that increased folic acid intake among women of childbearing age may decrease the prevalence of trisomy 21 and other aneuploidies. Methods: The prevalence of aneuploidies from 1990 through 1999 was compared with folic acid use in women of childbearing age in South Carolina. Results: Folic acid use and the prevalence of all aneuploidies significantly increased during this period. Conclusion: Increased folic acid utilization in South Carolina was not associated with decreased prevalence of trisomy 21 or other aneuploidies.

Research has provided evidence of the role of multivitamin supplementation in the prevention of neural tube defects (NTD). Failure of the neural tube to close is one of the most frequent and severe human developmental defects. The etiology of NTD is complex, encompassing genetic, dietary and environmental factors. The purpose of this study was to explore the relationship between maternal dietary intake of methionine and the risk of having a NTD-affected pregnancy. We hypothesized that women with high maternal dietary methionine intake were at a decreased risk for a NTD. Combinations of methionine, folate and vitamin B-12 intakes and NTD risk were also examined. Data from a 5-y, population-based, case-control study of 170 NTD-affected pregnancies and 269 controls were provided by the South Carolina NTD Surveillance, Prevention, and Research Project. There was a 30-55% lower NTD risk among women whose average daily dietary intake of methionine was greater than the lowest quartile of intake (>1580 mg/d). The odds ratios associated with the three quartiles of methionine intake > 1580 mg/d after adjusting for energy, race and body mass index were 0.72 (P < 0.07), 0.68 (P < 0.07) and 0.45 (P < 0.06), respectively. These findings indicate that a reduction in the risk of having a NTD-affected pregnancy is associated with maternal dietary intake of methionine (3 mo pre- to 3 mo postconception). This finding is consistent with the hypothesis that methionine plays a role in the etiology of NTD and suggests the need for further research in the area of maternal diet and pregnancy.

Reliable techniques have been developed to produce large numbers of mitotic cells and to collect them at metaphase in order to visualize individual chromosomes. After cell culture and spreading of the metaphases onto slides, the chromosomes are stained to produce unique banding patterns or to reveal specialized structures. Molecular techniques have been developed to identify submicroscopic rearrangements and to compare karyotypes of different species. Keywords: chromosome banding; chromosome spreading; fluorescence in situ hybridization; high resolution banding; metaphase spreads; sister chromatid exchange

Structural chromosome rearrangements are changes in the physical structure of chromosomes that may result in birth defects, mental retardation and increased risk for infertility or pregnancy loss. Keywords: cytogenetics; inversions; insertions; deletions; duplications; isochromosomes; ring chromosomes; aneusomy; karyotype; contiguous gene syndromes; reciprocal translocations; robertsonian translocations; quadrivalent

PURPOSE: Research in the last 40 years has provided evidence of the role of dietary nutrients in the development of NTDs. Failure of the neural tube to close is one of the most frequent and severe fetal developmental defects. The etiology of NTDs is complex encompassing genetic, dietary, and environmental factors. With regard to diet, it appears that in humans, a combination of low levels of methionine, folate, and Vitamin B 12 may lead to the occurrence of NTDs. The purpose of this study was to explore the relationship between maternal dietary intake of methionine and the risk of having a NTD affected pregnancy. METHODS: It was hypothesized that women with high maternal dietary methionine intake were at a decreased risk for NTDs. Combinations of methionine and folate without supplements, methionine and folate with supplements, and methionine and Vitamin B 12 and NTD risk were also examined. Data from a case-control study of 170 NTD-affected pregnancies and 269 controls were provided by a CDC sponsored NTD Surveillance, Prevention, and Research Project. RESULTS: There was an approximately 30–55% reduction in NTD risk among women whose average daily dietary intake of methionine was greater than the lowest quartile of intake (>1580 mg/day). The odds ratios (95% CI) associated with the 3 quartiles of methionine intake greater than 1580 mg/day after adjusting for Kcal, race, and BMI were 0.72 (0.4030–1.288), 0.68 (0.3390–1.347), and 0.45 (0.1830–1.088). CONCLUSIONS: These findings indicate a reduction in the risk of having a NTD affected pregnancy is associated with maternal periconceptional dietary intake of methionine.