410 research outputs found
Evaluation of a novel assay for detection of the fetal marker RASSF1A: facilitating improved diagnostic reliability of noninvasive prenatal diagnosis
No full textBackgroundAnalysis of cell free fetal (cff) DNA in maternal plasma is used routinely for non invasive prenatal diagnosis (NIPD) of fetal sex determination, fetal rhesus D status and some single gene disorders. True positive results rely on detection of the fetal target being analysed. No amplification of the target may be interpreted either as a true negative result or a false negative result due to the absence or very low levels of cffDNA. The hypermethylated RASSF1A promoter has been reported as a universal fetal marker to confirm the presence of cffDNA. Using methylation-sensitive restriction enzymes hypomethylated maternal sequences are digested leaving hypermethylated fetal sequences detectable. Complete digestion of maternal sequences is required to eliminate false positive results.MethodscfDNA was extracted from maternal plasma (n = 90) and digested with methylation-sensitive and insensitive restriction enzymes. Analysis of RASSF1A, SRY and DYS14 was performed by real-time PCR.ResultsHypermethylated RASSF1A was amplified for 79 samples (88%) indicating the presence of cffDNA. SRY real time PCR results and fetal sex at delivery were 100% accurate. Eleven samples (12%) had no detectable hypermethylated RASSF1A and 10 of these (91%) had gestational ages less than 7 weeks 2 days. Six of these samples were male at delivery, five had inconclusive results for SRY analysis and one sample had no amplifiable SRY.ConclusionUse of this assay for the detection of hypermethylated RASSF1A as a universal fetal marker has the potential to improve the diagnostic reliability of NIPD for fetal sex determination and single gene disorders
Noninvasive prenatal testing for aneuploidy – ready for prime time?
No full textNoninvasive prenatal diagnosis using cell-free fetal DNA in the maternal plasma is moving into routine clinical practice for some indications. Here we discuss exciting developments in noninvasive prenatal diagnosis for aneuploidy afforded by recent publications, including 2 papers published in this journal, and highlight some of the issues that need to be considered before these tests can be implemented as part of routine antenatal care
Prenatal evaluation of fetal neck masses in preparation for the EXIT procedure: the value of pulmonary Doppler ultrasonography (PDU)
No full textSonographic demonstration of normal tracheal diameter and breathing-related lung fluid flow at 30 weeks' gestation in a fetus with a giant neck mass confirmed patent airways, thus avoiding an EXIT procedure
The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature
No full textThe clinical utility of microarray technologies when used in the context of prenatal diagnosis lies in the technology's ability to detect submicroscopic copy number changes that are associated with clinically significant outcomes. We have carried out a systematic review of the literature to calculate the utility of prenatal microarrays in the presence of a normal conventional karyotype. Amongst 12?362 cases in studies that recruited cases from all prenatal ascertainment groups, 295/12?362 (2.4%) overall were reported to have copy number changes with associated clinical significance (pCNC), 201/3090 (6.5%) when ascertained with an abnormal ultrasound, 50/5108 (1.0%) when ascertained because of increased maternal age and 44/4164 (1.1%) for all other ascertainment groups (e.g. parental anxiety and abnormal serum screening result). When additional prenatal microarray studies are included in which ascertainment was restricted to fetuses with abnormal ultrasound scans, 262/3730 (7.0%) were reported to have pCNCs
Evaluation of Array Comparative genomic Hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation
No full textBackground: Current pathways for testing fetuses at increased risk of a chromosomal anomaly because of an ultrasound anomaly involve karyotyping after rapid aneuploidy exclusion. Chromosomal microarray (CMA) may detect more clinically significant chromosomal imbalances than karyotyping but evidence to guide UK health service providers on whether or not CMA should replace karyotyping is limited. Objectives: (1) To compare detection rates of copy number variants (CNVs) and laboratory turnaround times (TATs) by karyotyping and CMA in fetuses with ultrasound anomalies, (2) to calculate test costs and the cost per additional pathogenic CNV detected by CMA relative to karyotyping and (3) to determine what factors influence parents’ and health professionals’ choice and decision-making about CMA. Design: A multicentre experimental research cohort study with an additional cost analysis. Setting: A total of 20 fetal medicine units and nine cytogenetic laboratories across England and Wales. Participants: Women with a fetus undergoing quantitative fluorescent polymerase chain reaction (QF-PCR) and karyotyping for clinical indications with (1) one or more structural anomalies identified on ultrasound or (2) an isolated nuchal translucency (NT) of ≥ 3.5 mm. Interventions: Karyotyping and CMA after exclusion of major chromosomal anomalies by QF-PCR. The array design consisted of 8-plex 60,000 60-mer oligonucleotides with a backbone resolution of ≈75 kb. Main outcome measures: Rates of abnormal karyotypes and pathogenic CNVs and variants of unknown significance on CMA. Laboratory TATs for karyotyping and CMA. Costs of karyotyping and CMA and cost per additional pathogenic CNV detected by CMA. Parent and health professional attitudes to CMA. Results: Out of the 1718 probands recruited, 1123 cases with normal QF-PCR and both karyotype and CMA were available for analysis. In the group with structural anomalies (n = 629), CMA detected more CNVs [6.8%, 95% confidence interval (CI) 4.4% to 9.3%] and more pathogenic CNVs (3.5%, 95% CI 1.5% to 5.5%) than karyotyping. In the increased NT group (n = 494), CMA detected more CNVs (4.5%, 95% CI 1.8% to 7.1%) than karyotyping but not more pathogenic CNVs. Compared with karyotyping, median TAT was 3 days [interquartile range (IQR) 0–13 days] longer with CMA but when actual set-up to reporting times were compared, CMA was 5 days (IQR 2–8 days) quicker. Cost calculations of the respective pathways indicated that, per patient, CMA is on average £113 more costly than karyotyping. The incremental cost per extra pathogenic CNV detected by CMA was greater in the increased NT than the structural anomaly group (£9439 vs. £3635). Qualitative evaluation suggested that parents find CMA acceptable, despite the uncertainties it may introduce, and that in the main it is acceptable to health professionals and commissioners. Conclusions: CMA is a robust, acceptable and probably cost-effective method to detect more clinically significant chromosomal imbalances in the anomalous fetus. The results suggest that CMA should replace karyotyping in these care pathways. Future work: The application of CMA (and exome sequencing) on cell-free DNA in maternal plasma. Trial registration: Current Controlled Trials ISRCTN01058191. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and NIHR partnership. The funder had no role in the identification, design and conduct of the study and the reporting of the analysis. The funder did recommend the inclusion of the cell-free DNA aspects of the EACH study. Funding was also received from the Great Ormond Street Biomedical Research Centre
Equity and growth in developing countries : old and new perspectives on the policy issues
No full textThe"stylized fact"that distribution must get worse with economic growth in poor countries before it can get better turns out not to be a fact at all. Growth's effects on inequality can go either way and are contingent on several other factors. The authors found no sign in the new cross-country data they assembled that growth has any systematic impact on inequality. Possibly measurement errors confound the true relationship, but they think it more likely that the relationship between growth and distribution is not as simple as some theories have held. Since distribution does not worsen, growth reduces absolute poverty. Indeed, absolute poverty measures typically respond quite elastically to growth, and the benefits are certainly not confined to those near typical poverty lines. Of course, one cannot say that growth always benefits the poor or that none of the poor lose from pro-growth policy reform. Only aggregate effects are studied. But for 17 of the 20 countries for which they assemble quite good data (from at least two surveys since the mid-1980s), the mean and the proportion of people living below $1 a day moved in opposite directions. The gains to poor people from a distribution-neutral growth process will tend to be lower, the higher the extent of initial inequality. A smaller share of total income must imply a smaller absolute gain from a given increment to total income. Compensatory direct interventions can be important, provided they are integrated into a framework of fiscal and monetary discipline. The evidence does not suggest that growth is always distribution-neutral, and it would be wrong to conclude that changes in distribution are of little consequence. The point is not that distribution is irrelevant or that it never changes, but that its changes are roughly uncorrelated with economic growth. There is no intrinsic tradeoff between long-run aggregate efficiency and overall equity. Policies aimed at helping the poor accumulate productive assets--especially policies to improve schooling, health, and nutrition--when adopted in a relatively nondistorted framework, are important instruments for achieving higher growth.Services&Transfers to Poor,Environmental Economics&Policies,Economic Conditions and Volatility,Health Monitoring&Evaluation,Public Health Promotion,Achieving Shared Growth,Inequality,Governance Indicators,Safety Nets and Transfers,Rural Poverty Reduction
Fetal central nervous system anomalies: When should we offer exome sequencing?
No full textOBJECTIVE: To investigate the detection of pathogenic variants using exome sequencing in an international cohort of fetuses with central nervous system (CNS) anomalies. METHODS: We reviewed trio exome sequencing (ES) results for two previously reported unselected cohorts (Prenatal Assessment of Genomes and Exomes (PAGE) and CUIMC) to identify fetuses with CNS anomalies with unremarkable karyotypes and chromosomal microarrays. Variants were classified according to ACMG guidelines and association of pathogenic variants with specific types of CNS anomalies explored. RESULTS: ES was performed in 268 pregnancies with a CNS anomaly identified using prenatal ultrasound . Of those with an isolated, single, CNS anomaly, 7/97 (7.2%) had a likely pathogenic/pathogenic (LP/P) variant. This includes 3/23 (13%) fetuses with isolated mild ventriculomegaly and 3/10 (30%) fetuses with isolated agenesis of the corpus callosum. Where there were multiple anomalies within the CNS, 12/63 (19%) had LP/P variants. Of the 108 cases with CNS and other organ system anomalies, 18 (16.7%) had LP/P findings. CONCLUSION: ES is an important tool in the prenatal evaluation of fetuses with any CNS anomaly. The rate of LP/P variants tends to be highest in fetuses with multiple CNS anomalies and multisystem anomalies, however, ES may also be of benefit for isolated CNS anomalies
Ultrasound examination: The key to maximising the benefits of advances in molecular diagnostic technologies
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