Prenatal Diagnosis: Screening and Diagnostic Tools.
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ABSTRACT:
SUBMITTER: Carlson LM
PROVIDER: S-EPMC5548328 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:We report on the validation and implementation of the HumanCytoSNP-12 array (Illumina) (HCS) in prenatal diagnosis. In total, 64 samples were used to validate the Illumina platform (20 with a known (sub) microscopic chromosome abnormality, 5 with known maternal cell contamination (MCC) and 39 normal control samples). There were no false-positive or false-negative results. In addition to the diagnostic possibilities of arrayCGH, the HCS allows detection of regions of homozygosity (ROH), triploidy and helps recognising MCC. Moreover, in two cases of MCC, a deletion was correctly detected. Furthermore we found out that only about 50 ng of DNA is required, which allows a reporting time of only 3 days. We also present a prospective pilot study of 61 fetuses with ultrasound abnormalities and a normal karyotype tested with HCS. In 4 out of 61 (6.5%) fetuses, a clinically relevant abnormality was detected. We designed and present pre-test genetic counselling information on categories of possible test outcomes. On the basis of this information, about 90% of the parents chose to be informed about adverse health outcomes of their future child at infancy and childhood, and 55% also about outcomes at an adult stage. The latter issue regarding the right of the future child itself to decide whether or not to know this information needs to be addressed.
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Project description:The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population.
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Project description:Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%-10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US. Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel. Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV. Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.
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Project description:Background and aims: X-linked ichthyosis (XLI) is a common recessive genetic disease caused by the deletion of steroid sulfatase (STS) in Xp22.31. Maternal copy-number deletions in Xp22.31 (covering STS) can be considered an incidental benefit of genome-wide cell-free DNA profiling. Here, we explored the accuracy and clinical value of maternal deletions in Xp22.31 during non-invasive prenatal screening (NIPS). Materials and methods: We evaluated 13,156 pregnant women who completed NIPS. The maternal deletions in Xp22.31 revealed by NIPS were confirmed with maternal white blood cells by chromosome microarray analysis (CMA) or copy-number variation sequencing (CNV-seq). Suspected positive women pregnant with male fetuses were informed and provided with prenatal genetic counseling. Results: Nineteen maternal deletions in Xp22.31 covering STS were detected by NIPS, which were all confirmed, ranging in size from 0.61 to 1.77 Mb. Among them, eleven women with deletions in male fetuses accepted prenatal diagnoses, and finally nine cases of XLI were diagnosed. The nine XLI males had differing degrees of skin abnormalities, and of them, some male members of ten families had symptoms associated with XLI. Conclusion: NIPS has the potential to detect clinically significant maternal X chromosomal CNVs causing XLI, which can guide the prenatal diagnosis of X-linked ichthyosis and reflect the family history, so as to enhance pregnancy management as well as children and family members' health management.
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Project description:BackgroundFrailty is associated with multiple adverse outcomes in stage-5 chronic kidney disease (CKD-5) and upwards of one third of people receiving haemodialysis (HD) are frail. While many frailty screening methods are available in both uremic and non-uremic populations, their implementation in clinical settings is often challenged by time and resource constraints. In this study, we explored the diagnostic accuracy of time-efficient screening tools in people receiving HD.MethodsA convenience sample of 76 people receiving HD [mean age = 61.1 years (SD = 14), 53.9% male] from three Renal Units were recruited for this cross-sectional study. Frailty was diagnosed by means of the Fried phenotype. Physical performance-based screening tools encompassed handgrip strength, 15-ft gait speed, timed up and go (TUG), and five-repetition sit to stand (STS-5) tests. In addition, participants completed the SF-36 Health Survey, the short-form international physical activity questionnaire and the Tinetti falls efficacy scale (FES) as further frailty-related measures. Outcome measures included the area under the curve (AUC), sensitivity, specificity, positive (PPV) and negative predictive values (NPV). The diagnostic performance of screening tools in assessing fall-risk was also investigated.ResultsOverall, 36.8% of participants were classified as frail. All the examined instruments could significantly discriminate frailty status in the study population. Gait speed [AUC = 0.89 (95%CI: 0.81-0.98), sensitivity = 75%, specificity = 93%] and TUG [AUC = 0.90 (95%CI: 0.80-0.99), sensitivity = 89%, specificity = 85%] exhibited the highest diagnostic accuracy. There was a significant difference in gait speed AUC (20%, p = 0.013) between participants aged 65 years or older (n = 36) and those under 65 years of age (n = 40), with better discriminating performance in the younger sub-group. The Tinetti FES was the only instrument showing good diagnostic accuracy (AUCs≥0.80) for both frailty (sensitivity = 82%, specificity = 79%) and fall-risk (sensitivity = 82%, specificity = 71%) screening.ConclusionsThis cross-sectional study revealed that time- and cost-efficient walking performance measures can accurately be used for frailty-screening purposes in people receiving HD. While self-selected gait speed had an excellent performance in people under 65 years of age, TUG may be a more suitable screening method for elderly patients (≥65 years). The Tinetti FES may be a clinically useful test when physical testing is not achievable.
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Project description:PurposeTo validate three early ejaculation diagnostic tools, and propose a new tool for diagnosis in line with proposed changes to diagnostic criteria. Significant changes to diagnostic criteria are expected in the near future. Available screening tools do not necessarily reflect proposed changes.Materials and methodsData from 148 diagnosed early ejaculation patients (M age = 42.8) and 892 controls (M age = 33.1 years) from a population-based sample were used. Participants responded to three different questionnaires (Premature Ejaculation Profile; Premature Ejaculation Diagnostic Tool; Multiple Indicators of Premature Ejaculation). Stopwatch measured ejaculation latency times were collected from a subsample of early ejaculation patients. We used two types of responses to the questionnaires depending on the treatment status of the patients 1) responses regarding the situation before starting pharmacological treatment and 2) responses regarding current situation. Logistic regressions and Receiver Operating Characteristics were used to assess ability of both the instruments and individual items to differentiate between patients and controls.ResultsAll instruments had very good precision (Areas under the Curve ranging from .93-.98). A new five-item instrument (named CHecklist for Early Ejaculation Symptoms - CHEES) consisting of high-performance variables selected from the three instruments had validity (Nagelkerke R (2) range .51-.79 for backwards/forwards logistic regression) equal to or slightly better than any individual instrument (i.e., had slightly higher validity statistics, but these differences did not achieve statistical significance). Importantly, however, this instrument was more in line with proposed changes to diagnostic criteria.ConclusionsAll three screening tools had good validity. A new 5-item diagnostic tool (CHEES) based on the three instruments had equal or somewhat more favorable validity statistics compared to the other three tools, but is more in line with recently proposed diagnostic criteria.
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