What women want: General population perspectives and access to preconception expanded carrier screening.

OBJECTIVE: Expanded carrier screening (ECS) assesses the risk of individuals and couples of having a child affected with a set of genetic conditions. Carriers have options available to optimize pregnancy outcomes based on personal values and preferences. The greatest range of options is available prior to pregnancy, therefore professional societies recommend this screening be performed preconception. This study aimed to assess awareness of, and interest in, ECS in women preconception. Additionally, it aimed to evaluate preferences for timing and location of education and availability of ECS. METHODS: A total of 260 nulliparous women from the general population were surveyed through Qualtrics, a national market research survey platform. Data were delineated using descriptive statistics. RESULTS: Of this cohort, 43.5% reported being aware of ECS prior to the survey and 77.8% indicated interest. Those previously aware were first informed by family, friends, or independent online research. Interest was primarily driven by a desire for reassurance and to make informed decisions about future pregnancies. Interested respondents indicated a willingness to request testing from providers. Participants showed a preference for education and access from a healthcare provider in person. CONCLUSION: These findings provide insight regarding when and where to best educate and reach women prior to pregnancy about ECS to maximize pregnancy outcomes.

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

OBJECTIVE: This study aimed to assess the efficacy of first-trimester aneuploidy screening in a single clinical setting. METHODS: Maternal age, nuchal translucency, and maternal serum levels of pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin comprised first-trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18. RESULTS: Of the 23 329 first-trimester screenings, 6.3% were screen positive: 5.7% for Down syndrome only, 0.4% for trisomies 13/18 only, and 0.3% for Down syndrome and trisomies 13/18. An abnormal karyotype was present in 3.9% of screen positives for Down syndrome, 13.8% of screen positives for trisomies 13/18, and 45.9% of screen positives for both Down syndrome and trisomies 13/18. Of the 97 pregnancies found to have an abnormal karyotype, 29.9% had chromosome abnormalities other than trisomy 13, 18, or 21, with expected clinical outcomes ranging from likely benign to uniformly lethal. CONCLUSION: As expected, first-trimester screening is effective for detecting aneuploidy for chromosomes 13, 18, and 21; however, a significant number of chromosomally abnormal pregnancies initially identified by first-trimester screening have a different karyotype. With the possible exception of 47,XYY and 45,X, the dataset suggested that these different chromosome complements were likely to be randomly distributed. Nevertheless, prior to diagnostic testing, prospective parents should be counseled concerning the possibility of a chromosome abnormality other than the trisomies 13, 18, or 21.

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

PURPOSE OF REVIEW: First trimester screening is presently offered to all pregnant women as a means of prenatal screening for Down syndrome, trisomy 18, and trisomy 13. Nuchal translucency measurement is a fundamental component of the screening protocol. A woman whose fetus' nuchal translucency is greater than the 95th percentile is also at increased risk for a multiplicity of other adverse pregnancy and pediatric outcomes, and as a consequence, counseling of patients about their testing options and range of pregnancy outcomes has become complex and difficult. RECENT FINDINGS: The increased risk for chromosome abnormalities, congenital heart malformations, and pregnancy loss in the presence of an increased nuchal translucency is well documented. What has not been clearly defined is the incidence of other genetic syndromes, congenital defects, and adverse pregnancy and pediatric outcomes in the presence of increased nuchal translucency. Currently, Noonan syndrome is the only molecular genetic condition that has been shown to have a clear association with the finding of increased nuchal translucency in the first trimester. SUMMARY: This article reviews the current literature on outcomes in pregnancies with an increased nuchal translucency and a normal karyotype. We summarize the range of outcomes detected in the first trimester with recommendations for further prenatal testing and counseling of patients.

Genetic assessment following increased nuchal translucency and normal karyotype.

OBJECTIVE: The objective of this study was to assess the first formal approach for monitoring genetic/developmental syndromes associated with the presence of an increased nuchal translucency (NT) thickness (>3 mm) in the first trimester of pregnancy. METHODS: Multiple technologies-a DNA chip using the APEX technology, qPCR, microfluidic PCR, and sequencing-were applied to assay 310 mutations across five conditions-Noonan syndrome, congenital adrenal hyperplasia, spinal muscular atrophy (SMA), DiGeorge syndrome, and Smith-Lemli Opitz syndrome. RESULTS: We report the results of assessing the first 120 patients in which 8 cases of Noonan syndrome were detected as well as an unusually high rate of heterozygosity for SMA. CONCLUSION: While testing for Noonan syndrome in association with increased NT appears warranted, the reported association of the remaining four genetic syndromes is likely to be weak and possibly insignificant.

Comprehensive arrayed primer extension array for the detection of 59 sequence variants in 15 conditions prevalent among the (Ashkenazi) Jewish population.

In the Ashkenazi Jewish population, serious and lethal genetic conditions occur with relatively high frequency. A single test that encompasses the majority of population-specific mutations is not currently available. For comprehensive carrier screening and molecular diagnostic purposes, we developed a population-specific and inclusive microarray. The arrayed primer extension genotyping microarray carries 59 sequence variant detection sites, of which 53 are detectable bi-directionally. These sites represent the most common variants in Tay-Sachs disease, Bloom syndrome, Canavan disease, Niemann-Pick A, familial dysautonomia, torsion dystonia, mucolipidosis type IV, Fanconi anemia, Gaucher disease, factor XI deficiency, glycogen storage disease type 1a, maple syrup urine disease, nonsyndromic sensorineural hearing loss, familial Mediterranean fever, and glycogen storage disease type III. Several mutations in the selected disorders that are not prevalent per se in the Ashkenazi Jewish populations, as well pseudodeficiency alleles, are also included in the array. The initial technical evaluation of this microarray demonstrates that it is comprehensive, robust, sensitive, specific, and easily modifiable. This cost-effective array is based on a diversely applied platform technology and is suitable for both carrier screening and disease detection in Ashkenazi and Sephardic Jewish populations.

Fetal Cell Based Prenatal Diagnosis: Perspectives on the Present and Future.

The ability to capture and analyze fetal cells from maternal circulation or other sources during pregnancy has been a goal of prenatal diagnostics for over thirty years. The vision of replacing invasive prenatal diagnostic procedures with the prospect of having the entire fetal genome in hand non-invasively for chromosomal and molecular studies for both clinical and research use has brought many investigators and innovations into the effort. While the object of this desire, however, has remained elusive, the aspiration for this approach to non-invasive prenatal diagnosis remains and the inquiry has continued. With the advent of screening by cell-free DNA analysis, the standards for fetal cell based prenatal diagnostics have been sharpened. Relevant aspects of the history and the current status of investigations to meet the goal of having an accessible and reliable strategy for capturing and analyzing fetal cells during pregnancy are reviewed.

Are fetal cells in maternal plasma really there? We think they are.

We describe a single centrifugation procedure that resulted in the recovery of fetal cells in maternal blood in 77% of normal male pregnancies and in 87.5% of aneuploid pregnancies. There was an average yield of one fetal cell/1,993 maternal cells in normal pregnancies, which increased to one in 994, in aneuploid pregnancies.

Applying a test system for discriminating fetal from maternal cells.

OBJECTIVE: The objectives of this study were to enhance and apply a simple system capable of testing the capacity of putative, gender-independent fetal cell markers, individually and in combination, to discriminate between fetal and maternal cells. METHODS: Chorionic villi tissue obtained from 25 male pregnancies at 10 to 12 weeks' gestation served as the experimental group. Following removal of villi pieces for clinical use, unattached cells were collected by centrifugation of the CVS fluid, fixed in the tube, and used as a source of mixed fetal and maternal cells. Blood obtained from a fetus at 13 weeks' gestation served as a positive control. Peripheral blood from two adult males served as negative controls. Antibodies to three possible fetal markers were tested using immunohistochemical techniques: anti-Flk-1, anti-epsilon globin, and anti-CD71. Each antibody was used alone and in combination in conjunction with fluorescent in situ hybridization (FISH) of X and Y chromosomes to confirm that positively stained cells were in fact fetal in origin. RESULTS: On CVS samples, the average predictive value for anti-Flk-1 was 35.8%, 76.2% for anti-CD71, and 90.5% for anti-epsilon. The combination of anti-epsilon and anti-CD71 antibodies identifying a fetal cell was 87.2% and the combined use of single and double antibodies gave a value of 82.7%. The combination of anti-epsilon globin and anti-CD71 increased the sensitivity of identifying pure fetal blood cells from 63%, for anti-epsilon alone, and 67%, for anti-CD71 alone, to 86%. CONCLUSION: Although anti-Flk-1 has been reported to be a successful marker of fetal cells, the results in this test system did not support this finding. This work supports the use of CVS washings containing both fetal and maternal cells as a viable test system for assessing antigenic markers. The combination of anti-CD71 and anti-epsilon as fetal identifiers may increase the chances of identifying a fetal cell without compromising the predictive value.

Sex ratio: a biological perspective of 'Sex and the City'.

The primary sex ratio in humans differs remarkably from the theoretically expected equality of 1:1, and may be as high as 170 males to 100 females. A number of environmental, physiological and genetic factors have been observed to impact on the primary sex ratio: sexual behaviour, variation in hormonal concentrations, natural disasters, environmental pollutants and timing of conception. Nevertheless, no biological mechanism or interaction of factors has suitably explained this phenomenon, or that of the prenatal vulnerability of the male, the suspected higher sex ratio in spontaneous abortion and the male excesses in adult diseases related to the intrauterine environment. Knowledge of the environmental effects and causes of natural variation in the primary sex ratio will make possible its manipulation, which will have public health implications as well as cultural and social consequences.