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 Use of highly parallel snp genotyping for fetal diagnosisUSPTO Application #: 20080070792Title: Use of highly parallel snp genotyping for fetal diagnosis Abstract: The present invention provides apparatus and methods for enriching components or cells from a sample and conducting genetic analysis, such as SNP genotyping to provide diagnostic results for fetal disorders or conditions. (end of abstract) Agent: Wilson Sonsini Goodrich & Rosati - Palo Alto, CA, US Inventors: Roland Stoughton, Ravi Kapur, Barb Ariel Cohen USPTO Applicaton #: 20080070792 - Class: 506009000 (USPTO) The Patent Description & Claims data below is from USPTO Patent Application 20080070792. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 60/804,816, filed Jun. 14, 2006, which application is incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Analysis of specific cells can give insight into a variety of diseases. These analyses can provide non-invasive tests for detection, diagnosis and prognosis of diseases, thereby eliminating the risk of invasive diagnosis. For instance, social developments have resulted in an increased number of prenatal tests. However, the available methods today, amniocentesis and chorionic villus sampling (CVS) are potentially harmful to the mother and to the fetus. The rate of miscarriage for pregnant women undergoing amniocentesis is increased by 0.5-1%, and that figure is slightly higher for CVS. Because of the inherent risks posed by amniocentesis and CVS, these procedures are offered primarily to older women, i.e., those over 35 years of age, who have a statistically greater probability of bearing children with congenital defects. As a result, a pregnant woman at the age of 35 has to balance an average risk of 0.5-1% to induce an abortion by amniocentesis against an age related probability for trisomy 21 of less than 0.3%. [0003] Some non-invasive methods have already been developed to diagnose specific congenital defects. For example, maternal serum alpha-fetoprotein, and levels of unconjugated estriol and human chorionic gonadotropin can be used to identify a proportion of fetuses with Down's syndrome, however, these tests are not one hundred percent accurate. Similarly, ultrasonography is used to determine congenital defects involving neural tube defects and limb abnormalities, but is useful only after fifteen weeks' gestation. [0004] The methods of the present invention allow for the detection of fetal cells and fetal abnormalities when fetal cells are mixed with a population of maternal cells, even when the maternal cells dominate the mixture. SUMMARY OF THE INVENTION [0005] The presence of fetal cells within the blood of pregnant women offers the opportunity to develop a prenatal diagnostic that replaces amniocentesis and thereby eliminates the risk of today's invasive diagnosis. However, fetal cells represent a small number of cells against the background of a large number of maternal cells in the blood which make the analysis time consuming and prone to error. Current technologies and protocols for highly parallel SNP detection with DNA microarray readout result in inaccurate calls when there are too few starting DNA copies or when a particular allele represents a small fraction in the population of input DNA molecules. [0006] The present invention relates to methods for detecting a fetal abnormality by determining the ratio of the abundance of one or more maternal alleles to the abundance of one or more paternal alleles in the genomic DNA of a sample. The genomic region includes a single nucleotide polymorphism (SNP), which can preferably be an informative SNP. The SNP can be detected by methods that include using a DNA microarray, bead microarray, or high throughput sequencing. In some embodiments, determining the ratio involves detecting an abundance of a nucleotide base at a SNP position. In other embodiments, determining the ratio also comprises calculating error rate based amplification. Prior to determining the abundance of allele(s), the sample can be enriched for fetal cells. [0007] The method of detection is provided by highly parallel SNP detection that can be used to determine the ratios of abundance of maternal and paternal alleles at a plurality of genomic regions present in the sample. In some embodiments, the ratios of abundance are determined in at least 100 genomic regions, which can comprise a single locus, different loci, a single chromosome, or different chromosomes. In some embodiments, a first genomic region (SNP) analyzed is in a genomic region suspected of being trisomic or is trisomic and a second genomic region (SNP) analyzed is in a non-trisomic region or a region suspected of being non-trisomic. The ratio of alleles in the first genomic region can then be compared to the ratio of alleles in the second genomic region, and in some embodiments, the comparison is made by determining the difference in the means of the ratios in the first and second genomic regions. An increase in paternal abundance can be indicative of paternal trisomy, while an increase in maternal abundance can be indicative of maternal trisomy. Alternatively, an increase in paternal abundance or maternal abundance of one or more alleles is indicative of partial trisomy. The first and second genomic regions can be on the same or different chromosomes. [0008] In an embodiment, the invention provides for a method for detecting a fetal abnormality comprising comparing an abundance of one or more maternal alleles in a first genomic region in a maternal blood sample, where said genomic region is suspected of trisomy with an abundance of one or more maternal alleles in a second genomic region in said blood sample wherein said second genomic region is non-trisomic. Up to 20 ml of blood can be used to detect the fetal abnormality. The first genomic region that is suspected of trisomy and the second genomic region that is a non-trisomic region can each be present on chromosomes 13, 18, 21 and on the X chromosome. [0009] In some embodiments, a ratio of the abundance of the maternal alleles in the first genomic region to the abundance of the maternal alleles in the second genomic region can be determined and compared to a second ratio obtained for a control sample. The control sample can comprise a diluted portion of the maternal sample, which can be diluted by a factor of at least 1,000. [0010] In some embodiments, detecting the fetal abnormality further involves estimating the number of fetal cells present in the maternal sample. This can be performed by, e.g., ranking the alleles detected according to their abundance. The ranking can then be used to determine an abundance of one or more paternal alleles. In some embodiments, data models can be fitted for optimal detection of aneuploidy. The methods herein can be used to identify monoploidy, triploidy, tetraploidy, pentaploidy and other multiples of the normal haploid state. For example, the data models can be used to determine estimates for the fraction of fetal cells present in a sample and for detecting a fetal abnormality or condition. [0011] In some embodiments, the abundance of one or more paternal alleles can be compared to the abundance of the maternal alleles at one or more genetic regions. In other embodiments, one or more ratios of the abundance of the paternal allele(s) to the abundance of the maternal allele(s) at one or more genetic regions can be compared with an estimate fraction of fetal cells. A statistical analysis can be performed on the one or more ratios of the abundance of paternal alleles to the abundance of the maternal alleles to determine the presence of fetal DNA in the sample with a level of confidence that exceeds 90%. INCORPORATION BY REFERENCE [0012] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0013] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0014] FIG. 1 illustrates an overview of the process of the invention. [0015] FIGS. 2A-2D illustrates one embodiment of a size-based separation module. [0016] FIGS. 3A-3C illustrates one embodiment of an affinity separation module. [0017] FIG. 4 illustrates one embodiment of a magnetic separation module. [0018] FIG. 5 illustrates an overview for a typical parallel SNP genotyping assay. [0019] FIG. 6 illustrates the types of SNP calls that result depicting allele strengths at different loci. Continue reading... Full patent description for Use of highly parallel snp genotyping for fetal diagnosis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of highly parallel snp genotyping for fetal diagnosis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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