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Johnson K.L.,Tufts University | Scholl T.M.,Esoterix Genetic Laboratories LLC | Slonim D.K.,Tufts University | Wick H.C.,Tufts University
Human Genetics | Year: 2014

Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix® U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p < 0.0001); SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic/immune system, distinguishing the Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome. © 2014, Springer-Verlag Berlin Heidelberg.

Karimov C.B.,Massachusetts General Hospital | Moragianni V.A.,Beth Israel Deaconess Medical Center | Cronister A.,Esoterix Genetic Laboratories LLC | Srouji S.,Brigham and Womens Hospital | And 5 more authors.
Human Reproduction | Year: 2011

Background: The FMR1 premutation is associated with overt primary ovarian insufficiency (POI). However, its prevalence in women with occult POI (i.e. menstrual cycles, but impaired ovarian response) has not been examined. We hypothesized that both the FMR1 premutation and intermediate allele is more frequent in infertile women with occult POI than in controls, and that a repeat length cutoff might predict occult POI. Methods: All subjects were menstruating women <42 years old and with no family history of unexplained mental retardation, autism or fragile X syndrome. Cases had occult POI defined by elevated FSH or poor response to gonadotrophin therapy (n 535). Control subjects (n=521) had infertility from other causes or were oocyte donors. Prevalence of the FMR1 premutation and intermediate alleles was examined and allele length was compared between controls and women with occult POI. Results: The frequency of the premutation (7/535 versus 1/521; P< 0.05) and intermediate alleles (17/535 versus 7/521; P< 0.05) was higher in women with occult POI than in controls. The allele with the greatest number of CGG repeats was longer in women with occult POI compared with controls (32.7 ± 7.1 versus 31.6 ± 4.3; P< 0.01). A receiver operating characteristic curve examining repeat length as a test for occult POI had an area of 0.56 ± 0.02 (P< 0.01). A repeat cutoff of 45 had a specificity of 98, but a sensitivity of only 5 to identify occult POI. The positive predictive value was only 21 for a fertility population that has ∼22 of its patients with occult POI. Conclusions: The data suggest that FMR1 premutations and intermediate alleles are increased in women with occult POI. Thus, FMR1 testing should be performed in these women as some will have fragileX-associated POI. Although the FMR1 repeat lengths were longer in women with occult POI, the data do not support the use of a repeat length cutoff to predict occult POI. © 2011 The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Esoterix Genetic Laboratories LLC | Date: 2012-01-31

Methods for enriching specific microparticles, such as fetal microparticles or disease specific microparticles, in a biological sample are disclosed. In certain embodiments, the methods include combining a biological sample with a molecule that binds specific microparticles, and separating fractions of the biological sample, wherein the fraction that contains the binding molecule is enriched for the specific microparticles. Also disclosed are methods for enriching fetal nucleic acids by enriching fetal microparticles in a fraction of the biological sample and isolating nucleic acids from the enriched fraction. Methods for facilitating prenatal diagnosis of fetal chromosomal abnormalities are disclosed. In certain embodiments, the methods include combining a biological sample with a molecule that binds fetal microparticles, separating fractions of the biological sample, isolating nucleic acids from the fraction enriched for fetal microparticles, and analyzing the nucleic acids for the presence of a mutation.

Embodiments of the present invention provide methods for the enrichment of rare microparticles, cells, or nucleic acids from a complex mixture using serial size exclusion filtration. Also provided are less invasive methods for detecting chromosomal or genetic abnormalities in a fetus, by enriching fetal microparticles in maternal plasma using serial size exclusion filtration, and isolating and analyzing the fetal nucleic acids from the fetal microparticles. Methods for diagnosis of diseases such as cancer are also provided, including enriching disease specific microparticles in the patients plasma using serial size exclusion filtration, and isolating and analyzing the nucleic acids from the disease specific microparticles.

Esoterix Genetic Laboratories Llc and Genzyme | Date: 2010-09-07

Computer software for controlling and managing patient medical information; Computer software for creating searchable databases of patient medical information and data.

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