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Biochemical analysis of cultured chorionic villi for the prenatal diagnosis of peroxisomal disorders: biochemical thresholds and molecular sensitivity for maternal cell contamination detection.

ABSTRACT: The prenatal diagnosis of peroxisomal disorders is most often performed by biochemical analysis of cultured chorionic villus sample (CVS) or amniocytes. We aimed to (a) highlight the risk of maternal cell contamination (MCC) in biochemical prenatal diagnosis, (b) establish the threshold of these biochemical assays to MCC, and (c) document the sensitivity of PCR based genotyping of microsatellites for the detection of MCC in prenatal diagnosis of inborn errors by biochemical analysis.The threshold of each biochemical assay was assessed by co-cultivating fibroblasts from known affected and normal individuals. Genotypes for three polymorphic loci were determined by PCR and GeneScan analysis. The sensitivity of the molecular test was determined by DNA mixing experiments and isolation of DNA from co-cultivated fibroblasts.MCC was detected in 2.5% of at risk CVS cultures (n = 79). Co-cultivation of defective and normal fibroblasts demonstrated that the peroxisomal biochemical assays were accurate at 25% contamination. Very low level DNA or cell contamination (1-5%) was detectable by genotyping, but an allele did not yield a definitive peak based on morphology until approximately 10% contamination. Furthermore, we demonstrated that other inborn errors of metabolism might be more susceptible to diagnostic error by low level MCC.The sensitivity of the microsatellite analysis (> or =10%) is well within the threshold of peroxisomal biochemical assays. Although peroxisomal biochemical assays would not be predicted to introduce a false positive or negative result if MCC <10% were present but not recognised by molecular analysis, the same may not be true for other inborn errors of metabolism.

SUBMITTER: Steinberg S

PROVIDER: S-EPMC1735906 | biostudies-other | 2005 Jan

REPOSITORIES: biostudies-other

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Biochemical analysis of cultured chorionic villi for the prenatal diagnosis of peroxisomal disorders: biochemical thresholds and molecular sensitivity for maternal cell contamination detection.

Steinberg S S Katsanis S S Moser A A Cutting G G

Journal of medical genetics 20050101 1

<h4>Objectives</h4>The prenatal diagnosis of peroxisomal disorders is most often performed by biochemical analysis of cultured chorionic villus sample (CVS) or amniocytes. We aimed to (a) highlight the risk of maternal cell contamination (MCC) in biochemical prenatal diagnosis, (b) establish the threshold of these biochemical assays to MCC, and (c) document the sensitivity of PCR based genotyping of microsatellites for the detection of MCC in prenatal diagnosis of inborn errors by biochemical an ...[more]

PMID: 15635073

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Project description:To examine whether abnormal prenatal biochemical screening results are associated with an increased risk of premature cardiovascular disease after pregnancy.Population based cohort study.The entire province of Ontario, Canada, where healthcare is universally available.Women aged 12-55 years, without pre-existing cardiovascular disease, who underwent prenatal screening between 1993 and 2011. One pregnancy per woman was randomly selected.Low (?5th centile multiple of the median) serum total chorionic gonadotropin, unconjugated estriol, and pregnancy associated plasma protein A and high (?95th centile multiple of the median) alphafetoprotein and dimeric inhibin-A.Composite of hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral arterial disease or hospital admission for heart failure or dysrhythmia at least 365 days after pregnancy.Among 855?536 pregnancies, and after a median of 11.4 (interquartile range 6.8-17.5) years of follow-up, 6209 women developed the main cardiovascular disease outcome. Abnormal results for each of the five prenatal biochemical screening analytes, especially dimeric inhibin-A, were associated with a higher risk of cardiovascular disease. Women with an abnormally high dimeric inhibin-A (?95th centile) had the highest rate of cardiovascular disease (30 events or 8.3 per 10?000 person years versus 251 events or 3.8 per 10?000 person years for those <95th centile; multivariable adjusted hazard ratio 2.0, 95% confidence interval 1.4 to 3.0). Compared with women without any abnormal biochemical measure, the hazard ratio for the cardiovascular disease composite outcome was 1.2-1.3 times higher with one abnormal analyte and 1.5-2.0 times higher with two or more abnormal analytes.Women with abnormal prenatal biochemical screening results, especially for dimeric inhibin-A, may be at higher risk of cardiovascular disease. If these findings are replicated elsewhere, a massive amount of data exists that could aid in identifying women at higher risk of premature cardiovascular disease and that could be conveyed to them or their healthcare providers.

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Biochemical analysis of cultured chorionic villi for the prenatal diagnosis of peroxisomal disorders: biochemical thresholds and molecular sensitivity for maternal cell contamination detection.

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Biochemical analysis of cultured chorionic villi for the prenatal diagnosis of peroxisomal disorders: biochemical thresholds and molecular sensitivity for maternal cell contamination detection.

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