US20050164241A1 - Non-invasive detection of fetal genetic traits - Google Patents

Non-invasive detection of fetal genetic traits Download PDF

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US20050164241A1
US20050164241A1 US10964726 US96472604A US2005164241A1 US 20050164241 A1 US20050164241 A1 US 20050164241A1 US 10964726 US10964726 US 10964726 US 96472604 A US96472604 A US 96472604A US 2005164241 A1 US2005164241 A1 US 2005164241A1
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fetal
dna
sample
disorder
chromosome
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Sinuhe Hahn
Wolfgang Holzgreve
Bernhard Zimmermann
Ying Li
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Sequenom Inc
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Sinuhe Hahn
Wolfgang Holzgreve
Bernhard Zimmermann
Ying Li
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    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6806Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/156Polymorphic or mutational markers

Abstract

Blood plasma of pregnant women contains fetal and (generally>90%) maternal circulatory extracellular DNA. Most of said fetal DNA contains ≦500 base pairs, said maternal DNA having a greater size. Separation of circulatory extracellular DNA of <500 base pairs results in separation of fetal from maternal DNA. A fraction of a blood plasma or serum sample of a pregnant woman containing, due to size separation (e.g. by chromatography, density gradient centrifugation or nanotechnological methods), extracellular DNA substantially comprising ≦500 base pairs is useful for non-invasive detection of fetal genetic traits (including the fetal RhD gene in pregnancies at risk for HDN; fetal Y chromosome-specific sequences in pregnancies at risk for X chromosome-linked disorders; chromosomal aberrations; hereditary Mendelian genetic disorders and corresponding genetic markers; and traits decisive for paternity determination) by e.g. PCR, ligand chain reaction or probe hybridization techniques, or nucleic acid arrays.

Description

    BACKGROUND OF THE INVENTION
  • The presence of circulatory extracellular DNA in the peripheral blood is a well established phenomenon. In this context, it has been shown that in the case of a pregnant woman extracellular fetal DNA is present in the maternal circulation and can be detected in maternal plasma or serum. Studies have shown that this circulatory fetal genetic material can be used for the very reliable determination, e.g. by PCR (polymerase chain reaction) technology, of fetal genetic loci which are completely absent from the maternal genome. Examples of such fetal genetic loci are the fetal RhD gene in pregnancies at risk for HDN (hemolytic disease of the fetus and newborn) or fetal Y chromosome-specific sequences in pregnancies at risk for an X chromosome-linked disorder e.g. hemophilia or fragile X syndrome.
  • The determination of other, more complex fetal genetic loci (e.g. chromosomal aberrations such as aneuploidies or chromosomal aberrations associated with Down's syndrome, or hereditary Mendelian genetic disorders and, respectively, genetic markers associated therewith, such as single gene disorders, e.g. cystic fibrosis or the hemoglobinopathies) is, however, more problematic. The reason for this difficulty is that the major proportion (generally>90%) of the extracellular DNA in the maternal circulation is derived from the mother. This vast bulk of maternal circulatory extracellular DNA renders it difficult, if not impossible, to determine fetal genetic alternations such as those involved in chromosomal aberrations (e.g. aneuploidies) or hereditary Mendelian genetic disorders (e.g. cystic fibrosis or the hemoglobinopathies) from the small amount of circulatory extracellular fetal DNA.
  • SUMMARY OF THE INVENTION
  • An examination of circulatory extracellular fetal DNA and circulatory extracellular maternal DNA in maternal plasma has now shown that, surprisingly, the majority of the circulatory extracellular fetal DNA has a relatively small size of approximately 500 base pairs or less, whereas the majority of circulatory extracellular maternal DNA in maternal plasma has a size greater than approximately 500 base pairs. Indeed, in certain instances the circulatory DNA material which is smaller than approximately 500 base pairs appears to be almost entirely fetal. Circulatory extracellular fetal DNA in the maternal circulation has thus been found to be smaller in size (approximately 500 base pairs or less) than circulatory extracellular maternal DNA (greater than approximately 500 base pairs).
  • This surprising finding forms the basis of the present invention according to which separation of circulatory extracellular DNA fragments which are smaller than approximately 500 base pairs provides a possibility to enrich for fetal DNA sequences from the vast bulk of circulatory extracellular maternal DNA.
  • This selective enrichment, which is based on size discrimination of circulatory DNA fragments of approximately 500 base pairs or less, leads to a fraction which is largely constituted by fetal extracellular DNA. This permits the analysis of fetal genetic traits including those involved in chromosomal aberrations (e.g. aneuploidies or chromosomal aberrations associated with Down's syndrome) or hereditary Mendelian genetic disorders and, respectively, genetic markers associated therewith (e.g. single gene disorders such as cystic fibrosis or the hemoglobinopathies), the determination of which had, as mentioned above, so far proved difficult, if not impossible. Size separation of extracellular fetal DNA in the maternal circulation thus facilitates the non-invasive detection of fetal genetic traits, including paternally inherited polymorphisms which permit paternity testing.
  • Clinical Chemistry, 1999, Vol. 45(9), pages 1570-1572 and The Australian & New Zealand Journal of Obstetrics & Gynaecology, February 2003 (O2-2003), Vol. 43(1), pages 10-15 describe a sample of blood plasma of a pregnant woman in which extracellular fetal DNA of less than 500 base pairs is enriched by PCR, is separated by gel electrophoresis and fetal male DNA (fetal Y-chromosome-specific sequence) is detected.
  • The present invention provides
      • a fraction of a sample of the blood plasma or serum (which preferably is substantially cell-free) of a pregnant woman in which, as the result of said sample having been submitted to a size separation, the extracellular DNA present therein substantially consists of DNA comprising 500 base pairs or less;
      • the use of such sample-fraction for the non-invasive detection of fetal genetic traits; and
      • a process for performing non-invasive detection of fetal genetic traits which comprises subjecting a sample of the blood plasma or serum of a pregnant woman to a size separation so as to obtain a fraction of said sample in which the extracellular DNA present therein substantially consists of DNA comprising 500 base pairs or less, and determining in said sample-fraction the fetal genetic trait(s) to be detected.
  • Said serum or plasma sample is preferably substantially cell-free, and this can be achieved by known methods such as, for example, centrifugation or sterile filtration.
  • The size separation of the extracellular DNA in said serum or plasma sample can be brought about by a variety of methods, including but not limited to
      • chromatography or electrophoresis such as chromatography on agarose or polyacrylamide gels, ion-pair reversed-phase high performance liquid chromatography (IP RP HPLC, see Hecker K H, Green S M, Kobayashi K, J. Biochem. Biophys. Methods 2000 Nov. 20; 46(1-2): 83-93), capillary electrophoresis in a self-coating, low-viscosity polymer matrix (see Du M, Flanagan J H Jr, Lin B, Ma Y, Electrophoresis 2003 September; 24 (18): 3147-53), selective extraction in microfabricated electrophoresis devices (see Lin R, Burke D T, Burn M A, J. Chromatogr. A. 2003 Aug. 29; 1010(2): 255-68), microchip electrophoresis on reduced viscosity polymer matrices (see Xu F, Jabasini M, Liu S, Baba Y, Analyst. 2003 June; 128(6): 589-92), adsorptive membrane chromatography (see Teeters M A, Conrardy S E, Thomas B L, Root T W, Lightfoot E N, J. Chromatogr. A. 2003 Mar. 7; 989(1): 165-73) and the like;
      • density gradient centrifugation (see Raptis L, Menard H A, J. Clin. Invest. 1980 December; 66(6): 1391-9); and
      • methods utilising nanotechnological means such as microfabricated entropic trap arrays (see Han J, Craighead H G, Analytical Chemistry, Vol. 74, No. 2, Jan. 15, 2002) and the like.
  • The sample-fraction thus obtained not only permits the subsequent determination of fetal genetic traits which had already been easily detectable in a conventional manner such as the fetal RhD gene in pregnancies at risk for HDN (hemolytic disease of the fetus and the newborn), or fetal Y chromosome-specific sequences in pregnancies at risk for an X chromosome-linked disorder such as hemophilia, fragile X syndrome or the like, but also the determination of other, more complex fetal genetic loci, including but not limited to
      • chromosomal aberrations (e.g aneuploidies or Down's syndrome) or hereditary Mendelian genetic disorders and, respectively, genetic markers associated therewith (e.g. single gene disorders such as cystic fibrosis or the hemoglobinopathies); and
        • fetal genetic traits which may be decisive when paternity is to be determined.
  • Such determination of fetal genetic traits can be effected by methods such as, for example, PCR (polymerase chain reaction) technology, ligase chain reaction, probe hybridisation techniques, nucleic acid arrays (so-called “DNA chips”) and the like.
  • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The following Examples are further illustrating the invention but are not to be construed as limitating its scope in any way.
  • EXAMPLE 1 Detection of Male Fetal DNA in Maternal Plasma by Real-Time Quantitative Polymerase Chain Reaction (PCR) After Size Fractionation of DNA by Agarose Gel Electrophoresis
  • Materials and Methods
  • Subjects and Sample Processing
  • Seven women pregnant in the third trimester with a male fetus were recruited for this study. 16-18 ml blood samples were collected into EDTA tubes. 6-9 ml of plasma were obtained after centrifugation at 1600 g for 10 minutes and a second centrifugation of the supernatant at 16000 g for 10 minutes.
  • DNA Isolation
  • DNA from 5-7 ml plasma was extracted using the QIAgen Maxi kit, according to the manufacturers' protocol. DNA was eluted in a volume of 1.5 ml.
  • DNA Precipitation
    • 1. To the plasma DNA were added: 1/10 volume NaAc (3M, pH 5.2), 2 volumes absolute ethanol, MgCl2 to a final concentration of 0.01 M and Glycogen to a final concentration of 50 μg/ml. The solution was thoroughly mixed by vortexing.
    • 2. The solution was stored overnight at −70° C.
    • 3. The DNA was recovered by centrifugation at 20000 g for 30 minutes at 4° C.
    • 4. The supernatant was carefully removed and the pellet washed with 500 μl 70% ethanol.
    • 5. The pellet was air dried and dissolved in 35 μl distilled water.
  • DNA Separation
    • 1. A 1% agarose Gel (Invitrogen, Cat No: 15510-027) was prepared for DNA electrophoresis.
    • 2. 28 μl DNA solution were loaded on the gel.
    • 3. The gel was electrophoresed at 80 Volt for 1 hour.
    • 4. The Gel was cut into pieces corresponding to specific DNA sizes according to the DNA size markers (New England Biolabs, 100 bp ladder and Lamda Hind III digest). The DNA sizes contained by the specific gel fragments were: 90-300 bases, 300-500 bases, 500-1000 bases, 1.0-1.5 kilobases (“kb”), 1.5-23 kb and >23 kb.
    • 5. The DNA was purified from the agarose gel pieces using the QIAEX II Gel Extraction kit (Qiagen, Cat No. 20021) and eluted in 35 μl Tris-HCl (pH 8.0, 10 mM).
  • Real-Time PCR
  • Sequences from the Y chromosome (SRY) and from chromosome 12 (GAPDH gene) were amplified with the Applied Biosystems (ABI) 7000 Sequence Detection System by real-time quantitative PCR to quantify amounts of fetal and total DNA in the size-separated fractions. The TaqMan system for SRY consisted of the amplification primers SRY_Fwd: TCC TCA AAA GAA ACC GTG CAT and SRY_Rev: AGA TTA ATG GTT GCT AAG GAC TGG AT and a FAM labeled TaqMan MGB (Minor Groove Binder) probe SRY_MGB: TCC CCA CAA CCT CTT. The TaqMan System for the GAPDH gene consisted of the following primers and probe: GAPDH_Fwd: CCC CAC ACA CAT GCA CTT ACC, GAPDH_Rev: CCT AGT CCC AGG GCT TTG ATT and GAPDH_MGB: TAG GAA GGA CAG GCA AC.
  • TaqMan amplification reactions were set up in a total reaction volume of 25 μl, containing 6 μl of the sample DNA solution, 300 nM of each primer (HPLC purified, Mycrosynth, Switzerland) and 200 nM of each probe (ABI) at 1× concentration of the Universal PCR reaction mix (ABI). Each sample was analyzed in duplicate for each of the two amplification systems. A standard curve containing known amounts of genomic DNA was run in parallel with each analysis.
  • Thermal cycling was performed according to the following protocol: An initial incubation at 50° C. for 2 minutes to permit Amp Erase activity, 10 minutes at 95° C. for activation of AmpliTaq Gold, and 40 cycles of 1 minute at 60° C. and 15 seconds at 95° C.
  • Amplification data collected by the 7000 Sequence Detection System was quantified using the slope of the standard curve as calculated by the sequence detection software and the results of a standard DNA solution used in the dilution curve with similar DNA copy numbers as the sample reactions as a reference sample for copy number calculations.
  • Results
  • Table 1 shows that in the five pregnancies examined, DNA fragments originating from the fetus were almost completely of sizes smaller than 500 base pairs with around 70% being of fetal origin for sizes smaller than 300 bases.
  • These results demonstrate that free DNA of fetal origin circulating in the maternal circulation can be specifically enriched by size separation of the total free DNA in the maternal blood. Depending on the downstream application the DNA size chosen for the enrichment of fetal DNA will be smaller than 300 or smaller than 500 bases.
    TABLE 1
    % of fetal DNA % of maternal DNA
    Size of DNA in each fragment in each fragment
    <0.3 kb  73.2 (22.22-87.06)  26.8 (12.94-77.78)
    0.3-0.5 kb 18.95 (6.43-31.42) 81.05 (68.58-93.57)
    0.5-1 kb  2.81 (0.00-7.75) 97.19 (92.25-100)
    1.0-1.5 kB  0.00 (0.00-12.50)   100 (87.5-100)
    1.5-23 kb  0.00 (0.00-8.40)   100 (100-100)

    The abbreviation “kb” appearing in the first column of this table stands for 1000 base pairs, and the figures given in its second and the third column are the median values ofthe percentages and, in brackets, the ranges.
  • EXAMPLE 2 Detection of Fetal DNA After Agarose Gel Electrophoresis by Polymerase Chain Reaction (PCR) of Microsatellite Markers, also Called “Short Tandem Repeats” (STRs)
  • Materials and Methods
  • Subjects and Samples
  • 18 ml blood samples from pregnant women and 9 ml blood from their partners were collected into EDTA tubes and plasma separated by centrifugation as described in example 1. The maternal buffy coat (i.e. the white colored top layer of the cell pellet obtained after the first centrifugation of 1600 g for 10 min.) was washed twice with PBS.
  • DNA Isolation
  • DNA from the plasma was extracted using a modification of the High Pure DNA template kit from Roche, the whole sample was passed through the filter usually used for 200 μl using a vacuum. The DNA was eluted in a volume of 50 μl elution buffer.
  • Paternal DNA was extracted from 400 μl paternal whole blood, using the High Pure DNA template kit, and eluted into 100 μl. Maternal DNA was isolated from the buffy coat, using the High Pure DNA template kit, and eluted into 100 μl.
  • DNA Separation
  • The DNA was size-separated by electrophoresis on an agarose gel and purified as described in Example 1.
  • PCR Specific for Short Tandem Repeats
  • From the fraction of sizes smaller than 500 bases, sequences from tetranucleotide repeat markers on Chromosome 21 were amplified in a multiplex PCR reaction as described in Li et al. Clinical Chemistry 49, No. 4, 2003. Because of the low concentration of plasma DNA, the fetal DNA in maternal plasma was examined by using a semi-nested PCR protocol.
  • The maternal and paternal pairs were genotyped using total genomic DNA to monitor microsatellite markers on chromosome 21.
  • The STR markers used were:
      • D211 S11;
      • D21S1270;
      • D21S1432; and
      • D21S1435
  • The resulting DNA fragments were then size separated by capillary electrophoresis on a sequencer, and the peak areas representing each allele for a specific marker were measured by the software.
  • Results
    TABLE 2
    Detection of fetal alleles specific for the
    microsatellite marker (Short Tandem Repeat) D21S11 on
    chromosome 21
    Maternal Fetal alleles
    alleles detected detected
    (D21S11) (D21S11)
    Maternal 232 bp N/A
    genomic DNA 234 bp
    Total 232 bp No fetal
    extracellulear DNA 234 bp alleles detectable
    (unseparated)
    Size-separated 232 bp 228 bp
    extracellular DNA 234 bp 232 bp
    (<300 bp)
    Size-weparated 232 bp 228 bp
    extracellular DNA 234 bp 232 bp
    (300-500 bp)

    Only in the size-separated fractions (<300 bp and 300-500 bp) could the feral alleles for D21S11 be detected, namely the paternally inherited 228 bp allele and the maternally inherited 232 bp allele, i.e. one allele from each parent.
  • Discussion
  • Analysis of the STR fragments can allow for the detection of paternal alleles that are distinct in length from the maternal repeat sequences, and by calculating the ratios between the peak areas it can be possible to identify patterns that are not consistent with a normal fetal karyotype. The identification of paternal allele sizes of STRs in the maternal circulation can allow the detection of certain chromosomal aberrations non-invasively. Also paternity testing can be accomplished prenatal in a non-invasive manner.

Claims (22)

  1. 1. A fraction of a sample of the blood plasma or serum of a pregnant woman in which, as the result of said sample having been submitted to a size separation, the extracellular DNA present therein substantially consists of DNA comprising 500 base pairs or less.
  2. 2. A sample-fraction according to claim 1 which is substantially cell-free.
  3. 3. A sample-fraction according to claim 1, wherein the size separation was carried out by chromatography or electrophoresis, by density gradient centrifugation or by methods utilising nanotechnological means.
  4. 4. A sample-fraction according to claim 3, wherein the chromatography and, respectively, electrophoresis was chromatography on agarose or polyacrylamide gels, ion-pair reversed-phase high performance liquid chromatography (IP RP HPLC), capillary electrophoresis in a self-coating, low-viscosity polymer matrix, selective extraction in microfabricated electrophoresis devices, microchip electrophoresis on reduced viscosity polymer matrices or adsorptive membrane chromatography.
  5. 5. A sample-fraction according to claim 3, wherein the method utilizing nanotechnological means was making use of microfabricated entropic trap arrays.
  6. 6. The use of a sample-fraction according to claim 1 for the non-invasive detection of fetal genetic traits.
  7. 7. The use according to claim 6, wherein the fetal genetic trait to be detected is the fetal RhD gene in a pregnancy at risk for HDN (hemolytic disease of the fetus and the newborn) or a fetal Y chromosome-specific sequence in a pregnancy at risk for an X chromosome-linked disorder.
  8. 8. The use according to claim 6, wherein the fetal genetic trait to be detected is a chromosomal aberration, a hereditary Mendelian genetic disorder and, respectively, a genetic marker associated therewith, or a fetal genetic trait which may be decisive when paternity is to be determined.
  9. 9. The use according to claim 7, wherein the X chromosome-linked disorder is hemophilia or fragile X syndrome.
  10. 10. The use according to claim 8, wherein the chromosomal aberration is an aneuploidy.
  11. 11. The use according to claim 8, wherein the chromosomal aberration is associated with Down's syndrome.
  12. 12. The use according to claim 8, wherein the hereditary Mendelian genetic disorder is a single gene disorder.
  13. 13. The use according to claim 12, wherein the single gene disorder is cystic fibrosis or a hemoglobinopathy.
  14. 14. The use according to claim 6, wherein the detection of the fetal genetic traits is carried out by PCR (polymerase chain reaction) technology, ligand chain reaction or probe hybridisation techniques or by means of nucleic acid arrays.
  15. 15. A process for performing non-invasive detection of fetal genetic traits which comprises subjecting a sample of the blood plasma or serum of a pregnant woman to a size separation so as to obtain a fraction of said sample in which the extracellular DNA present therein substantially consists of DNA comprising 500 base pairs or less, and determining the fetal genetic trait(s) to be detected by submitting such fraction to PCR (polymerase chain reaction) technology, ligase chain reaction or probe hybridisation techniques, or to nucleic acid arrays.
  16. 16. A process according to claim 15, wherein the fetal genetic trait to be detected is the fetal RhD gene in a pregnancy at risk for HDN (hemolytic disease of the fetus and the newborn) or a fetal Y chromosome-specific sequence in a pregnancy at risk for an X chromosome-linked disorder.
  17. 17. A process according to claim 15, wherein the fetal genetic trait to be detected is a chromosomal aberration, a hereditary Mendelian genetic disorder and, respectively, a genetic marker associated therewith, or a fetal genetic trait which may be decisive when paternity is to be determined.
  18. 18. A process according to claim 16, wherein the X chromosome-linked disorder is hemophilia or fragile X syndrome.
  19. 19. A process according to claim 17, wherein the chromosomal aberration is an aneuploidy.
  20. 20. A process according to claim 17, wherein the chromosomal aberration is associated with Down's syndrome.
  21. 21. A process according to claim 17, wherein the hereditary Mendelian genetic disorder is a single gene disorder.
  22. 22. A process according to claim 21, wherein the single gene disorder is cystic fibrosis or a hemoglobinopathy.
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US11855558 US7838647B2 (en) 2003-10-16 2007-09-14 Non-invasive detection of fetal genetic traits
US13029995 US9580751B2 (en) 2003-10-16 2011-02-17 Non-invasive detection of fetal genetic traits
US13029999 US20110245482A1 (en) 2003-10-16 2011-02-17 Non-invasive detection of fetal genetic traits
US13557025 US20120302741A1 (en) 2003-10-16 2012-07-24 Non-invasive detection of fetal genetic traits
US13757637 US9738931B2 (en) 2003-10-16 2013-02-01 Non-invasive detection of fetal genetic traits
US13779300 US20130190483A1 (en) 2003-10-16 2013-02-27 Non-invasive detection of fetal genetic traits
US15653401 US20170321279A1 (en) 2003-10-16 2017-07-18 Non-invasive detection of fetal genetic traits

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US13029995 Division US9580751B2 (en) 2003-10-16 2011-02-17 Non-invasive detection of fetal genetic traits
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US13029999 Abandoned US20110245482A1 (en) 2003-10-16 2011-02-17 Non-invasive detection of fetal genetic traits
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140417A2 (en) 2006-05-31 2007-12-06 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
US20080020390A1 (en) * 2006-02-28 2008-01-24 Mitchell Aoy T Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US20080071076A1 (en) * 2003-10-16 2008-03-20 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US20080070792A1 (en) * 2006-06-14 2008-03-20 Roland Stoughton Use of highly parallel snp genotyping for fetal diagnosis
US20080096766A1 (en) * 2006-06-16 2008-04-24 Sequenom, Inc. Methods and compositions for the amplification, detection and quantification of nucleic acid from a sample
US20080220422A1 (en) * 2006-06-14 2008-09-11 Daniel Shoemaker Rare cell analysis using sample splitting and dna tags
US20090029377A1 (en) * 2007-07-23 2009-01-29 The Chinese University Of Hong Kong Diagnosing fetal chromosomal aneuploidy using massively parallel genomic sequencing
US20090203002A1 (en) * 2006-03-06 2009-08-13 Columbia University Mesenchymal stem cells as a vehicle for ion channel transfer in syncytial structures
US20090317817A1 (en) * 2008-03-11 2009-12-24 Sequenom, Inc. Nucleic acid-based tests for prenatal gender determination
US20090317797A1 (en) * 2005-01-18 2009-12-24 Institut National De La Sante Et De La Recherche Medicale (Inserm) Non-Invasive, Prenatal, In-Vitro Method for Detecting the Normal Healthy Condition, the Condition of a Healthy Carrier or the Condition of a Carrier Inflicted with Cystic Fibrosis
US20100112590A1 (en) * 2007-07-23 2010-05-06 The Chinese University Of Hong Kong Diagnosing Fetal Chromosomal Aneuploidy Using Genomic Sequencing With Enrichment
US20100124752A1 (en) * 2006-02-02 2010-05-20 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
US20100184043A1 (en) * 2006-02-28 2010-07-22 University Of Louisville Research Foundation Detecting Genetic Abnormalities
US20100184044A1 (en) * 2006-02-28 2010-07-22 University Of Louisville Research Foundation Detecting Genetic Abnormalities
US20100261188A1 (en) * 2006-12-07 2010-10-14 Biocept, Inc. Non-invasive prenatal genetic screen
US20110033862A1 (en) * 2008-02-19 2011-02-10 Gene Security Network, Inc. Methods for cell genotyping
WO2011034631A1 (en) 2009-09-16 2011-03-24 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses
US20110092763A1 (en) * 2008-05-27 2011-04-21 Gene Security Network, Inc. Methods for Embryo Characterization and Comparison
US20110105353A1 (en) * 2009-11-05 2011-05-05 The Chinese University of Hong Kong c/o Technology Licensing Office Fetal Genomic Analysis From A Maternal Biological Sample
WO2011054936A1 (en) 2009-11-06 2011-05-12 The Chinese University Of Hong Kong Size-based genomic analysis
US20110117548A1 (en) * 2006-02-28 2011-05-19 University Of Louisville Research Foundation, Inc. Detecting Fetal Chromosomal Abnormalities Using Tandem Single Nucleotide Polymorphisms
US20110129841A1 (en) * 2005-06-02 2011-06-02 Fluidigm Corporation Analysis using microfluidic partitioning devices
US20110130558A1 (en) * 2008-05-30 2011-06-02 Qiagen Gmbh Method for isolating nucleic acids
US20110178719A1 (en) * 2008-08-04 2011-07-21 Gene Security Network, Inc. Methods for Allele Calling and Ploidy Calling
WO2011156387A2 (en) 2010-06-07 2011-12-15 Esoterix Genetic Laboratories, Llc Enumeration of nucleic acids
US8137912B2 (en) 2006-06-14 2012-03-20 The General Hospital Corporation Methods for the diagnosis of fetal abnormalities
US8195415B2 (en) 2008-09-20 2012-06-05 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuploidy by sequencing
WO2012114075A1 (en) 2011-02-25 2012-08-30 University Of Plymouth Method for processing maternal and fetal dna
US8426122B2 (en) 2010-03-11 2013-04-23 Cellscape Corporation Method and device for identification of nucleated red blood cells from a maternal blood sample
WO2013075100A1 (en) * 2011-11-17 2013-05-23 Cellscape Corporation Methods, devices, and kits for obtaining and analyzing cells
US8450061B2 (en) 2011-04-29 2013-05-28 Sequenom, Inc. Quantification of a minority nucleic acid species
US8518228B2 (en) 2011-05-20 2013-08-27 The University Of British Columbia Systems and methods for enhanced SCODA
US8529744B2 (en) 2004-02-02 2013-09-10 Boreal Genomics Corp. Enrichment of nucleic acid targets
WO2014011928A1 (en) 2012-07-13 2014-01-16 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses
US8652780B2 (en) 2007-03-26 2014-02-18 Sequenom, Inc. Restriction endonuclease enhanced polymorphic sequence detection
US8682592B2 (en) 2005-11-26 2014-03-25 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
US8722336B2 (en) 2008-03-26 2014-05-13 Sequenom, Inc. Restriction endonuclease enhanced polymorphic sequence detection
US8771948B2 (en) 2009-04-03 2014-07-08 Sequenom, Inc. Nucleic acid preparation compositions and methods
US8825412B2 (en) 2010-05-18 2014-09-02 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US8852416B2 (en) 2008-02-01 2014-10-07 The University Of British Columbia Methods and apparatus for particle introduction and recovery
US8877028B2 (en) 2009-04-21 2014-11-04 The University Of British Columbia System and methods for detection of particles
US8962247B2 (en) 2008-09-16 2015-02-24 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses
US9163282B2 (en) 2010-05-18 2015-10-20 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US9186685B2 (en) 2012-01-13 2015-11-17 The University Of British Columbia Multiple arm apparatus and methods for separation of particles
US9228234B2 (en) 2009-09-30 2016-01-05 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US9340835B2 (en) 2013-03-15 2016-05-17 Boreal Genomics Corp. Method for separating homoduplexed and heteroduplexed nucleic acids
US9367663B2 (en) 2011-10-06 2016-06-14 Sequenom, Inc. Methods and processes for non-invasive assessment of genetic variations
US9424392B2 (en) 2005-11-26 2016-08-23 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
US9499870B2 (en) 2013-09-27 2016-11-22 Natera, Inc. Cell free DNA diagnostic testing standards
US9512477B2 (en) 2012-05-04 2016-12-06 Boreal Genomics Inc. Biomarker anaylsis using scodaphoresis
EP3103871A1 (en) 2008-09-16 2016-12-14 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnostic
US9534304B2 (en) 2004-02-02 2017-01-03 The University Of British Columbia Scodaphoresis and methods and apparatus for moving and concentrating particles
US9547748B2 (en) 2011-06-29 2017-01-17 Bgi Health Service Co., Ltd. Method for determining fetal chromosomal abnormality
US9598731B2 (en) 2012-09-04 2017-03-21 Guardant Health, Inc. Systems and methods to detect rare mutations and copy number variation
US9605313B2 (en) 2012-03-02 2017-03-28 Sequenom, Inc. Methods and processes for non-invasive assessment of genetic variations
US9677118B2 (en) 2014-04-21 2017-06-13 Natera, Inc. Methods for simultaneous amplification of target loci
US9840732B2 (en) 2012-05-21 2017-12-12 Fluidigm Corporation Single-particle analysis of particle populations
US9892230B2 (en) 2012-03-08 2018-02-13 The Chinese University Of Hong Kong Size-based analysis of fetal or tumor DNA fraction in plasma
US9902992B2 (en) 2012-09-04 2018-02-27 Guardant Helath, Inc. Systems and methods to detect rare mutations and copy number variation
US9920361B2 (en) 2012-05-21 2018-03-20 Sequenom, Inc. Methods and compositions for analyzing nucleic acid
US9920366B2 (en) 2013-12-28 2018-03-20 Guardant Health, Inc. Methods and systems for detecting genetic variants
US9926593B2 (en) 2009-12-22 2018-03-27 Sequenom, Inc. Processes and kits for identifying aneuploidy
US9984198B2 (en) 2011-10-06 2018-05-29 Sequenom, Inc. Reducing sequence read count error in assessment of complex genetic variations
US10011870B2 (en) 2016-12-07 2018-07-03 Natera, Inc. Compositions and methods for identifying nucleic acid molecules
US10083273B2 (en) 2005-07-29 2018-09-25 Natera, Inc. System and method for cleaning noisy genetic data and determining chromosome copy number
US10081839B2 (en) 2005-07-29 2018-09-25 Natera, Inc System and method for cleaning noisy genetic data and determining chromosome copy number
US10106836B2 (en) 2013-03-15 2018-10-23 The Chinese University Of Hong Kong Determining fetal genomes for multiple fetus pregnancies
US10113196B2 (en) 2010-05-18 2018-10-30 Natera, Inc. Prenatal paternity testing using maternal blood, free floating fetal DNA and SNP genotyping

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8024128B2 (en) * 2004-09-07 2011-09-20 Gene Security Network, Inc. System and method for improving clinical decisions by aggregating, validating and analysing genetic and phenotypic data
US20070027636A1 (en) * 2005-07-29 2007-02-01 Matthew Rabinowitz System and method for using genetic, phentoypic and clinical data to make predictions for clinical or lifestyle decisions
CA2632230A1 (en) * 2005-11-26 2007-05-31 Gene Security Network, Inc. System and method for cleaning noisy genetic data and using genetic, phentoypic and clinical data to make predictions
US8515679B2 (en) 2005-12-06 2013-08-20 Natera, Inc. System and method for cleaning noisy genetic data and determining chromosome copy number
US20070122823A1 (en) * 2005-09-01 2007-05-31 Bianchi Diana W Amniotic fluid cell-free fetal DNA fragment size pattern for prenatal diagnosis
US20070178501A1 (en) * 2005-12-06 2007-08-02 Matthew Rabinowitz System and method for integrating and validating genotypic, phenotypic and medical information into a database according to a standardized ontology
US20090053719A1 (en) * 2007-08-03 2009-02-26 The Chinese University Of Hong Kong Analysis of nucleic acids by digital pcr
EP2250497B1 (en) * 2008-02-18 2014-09-10 Genetic Technologies Limited Cell processing and/or enrichment methods
US20110262916A1 (en) * 2008-07-18 2011-10-27 Wen-Hua Fan Non-invasive fetal rhd genotyping from maternal whole blood
EP2421955A4 (en) 2009-04-21 2012-10-10 Genetic Technologies Ltd Methods for obtaining fetal genetic material
US20110312503A1 (en) 2010-01-23 2011-12-22 Artemis Health, Inc. Methods of fetal abnormality detection
EP2609219A4 (en) * 2010-08-24 2014-03-26 Bio Dx Inc Defining diagnostic and therapeutic targets of conserved free floating fetal dna in maternal circulating blood
US10131947B2 (en) * 2011-01-25 2018-11-20 Ariosa Diagnostics, Inc. Noninvasive detection of fetal aneuploidy in egg donor pregnancies
JP6013332B2 (en) * 2011-06-27 2016-10-25 オリンパス株式会社 Counting Method of target particles
GB2524948A (en) * 2014-03-07 2015-10-14 Oxford Gene Technology Operations Ltd Detecting Increase or Decrease in the Amount of a Nucleic Acid having a Sequence of Interest
KR20160010277A (en) 2014-07-18 2016-01-27 에스케이텔레콤 주식회사 Method for prediction of fetal monogenic genetic variations through next generation sequencing of maternal cell-free dna
US9850523B1 (en) 2016-09-30 2017-12-26 Guardant Health, Inc. Methods for multi-resolution analysis of cell-free nucleic acids

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674686A (en) * 1994-03-28 1997-10-07 Promega Corporation Allelic ladders for short tandem repeat loci
US20080071076A1 (en) * 2003-10-16 2008-03-20 Sequenom, Inc. Non-invasive detection of fetal genetic traits

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69624908D1 (en) * 1995-03-08 2003-01-02 Bioseparations Inc Method for erreicherung of populations of rare cells
GB9704444D0 (en) * 1997-03-04 1997-04-23 Isis Innovation Non-invasive prenatal diagnosis
WO2004079011A1 (en) 2003-02-28 2004-09-16 Ravgen, Inc. Methods for detection of genetic disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674686A (en) * 1994-03-28 1997-10-07 Promega Corporation Allelic ladders for short tandem repeat loci
US20080071076A1 (en) * 2003-10-16 2008-03-20 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US7838647B2 (en) * 2003-10-16 2010-11-23 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US20110245482A1 (en) * 2003-10-16 2011-10-06 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US20110251076A1 (en) * 2003-10-16 2011-10-13 Sequenom, Inc. Non-invasive detection of fetal genetic traits

Cited By (144)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9580751B2 (en) 2003-10-16 2017-02-28 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US20080071076A1 (en) * 2003-10-16 2008-03-20 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US9738931B2 (en) 2003-10-16 2017-08-22 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US7838647B2 (en) 2003-10-16 2010-11-23 Sequenom, Inc. Non-invasive detection of fetal genetic traits
US8529744B2 (en) 2004-02-02 2013-09-10 Boreal Genomics Corp. Enrichment of nucleic acid targets
US9534304B2 (en) 2004-02-02 2017-01-03 The University Of British Columbia Scodaphoresis and methods and apparatus for moving and concentrating particles
US9011661B2 (en) 2004-02-02 2015-04-21 Boreal Genomics, Inc. Enrichment of nucleic acid targets
US20090317797A1 (en) * 2005-01-18 2009-12-24 Institut National De La Sante Et De La Recherche Medicale (Inserm) Non-Invasive, Prenatal, In-Vitro Method for Detecting the Normal Healthy Condition, the Condition of a Healthy Carrier or the Condition of a Carrier Inflicted with Cystic Fibrosis
US20110129841A1 (en) * 2005-06-02 2011-06-02 Fluidigm Corporation Analysis using microfluidic partitioning devices
US20110143949A1 (en) * 2005-06-02 2011-06-16 Fluidigm Corporation Analysis using microfluidic partitioning devices
US9364829B2 (en) 2005-06-02 2016-06-14 Fluidigm Corporation Analysis using microfluidic partitioning devices
US10083273B2 (en) 2005-07-29 2018-09-25 Natera, Inc. System and method for cleaning noisy genetic data and determining chromosome copy number
US10081839B2 (en) 2005-07-29 2018-09-25 Natera, Inc System and method for cleaning noisy genetic data and determining chromosome copy number
US9424392B2 (en) 2005-11-26 2016-08-23 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
US9695477B2 (en) 2005-11-26 2017-07-04 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
US8682592B2 (en) 2005-11-26 2014-03-25 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
US9430611B2 (en) 2005-11-26 2016-08-30 Natera, Inc. System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals
EP2423334A2 (en) 2006-02-02 2012-02-29 The Board of Trustees of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US20100255493A1 (en) * 2006-02-02 2010-10-07 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
US20100256013A1 (en) * 2006-02-02 2010-10-07 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
US20100255492A1 (en) * 2006-02-02 2010-10-07 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
EP3002338A1 (en) 2006-02-02 2016-04-06 The Board of Trustees of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US8293470B2 (en) 2006-02-02 2012-10-23 The Board Of Trustees Of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US9777328B2 (en) 2006-02-02 2017-10-03 The Board Of Trustees Of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US20100124751A1 (en) * 2006-02-02 2010-05-20 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
US20100124752A1 (en) * 2006-02-02 2010-05-20 The Board Of Trustees Of The Leland Stanford Junior University Non-Invasive Fetal Genetic Screening by Digital Analysis
US9441273B2 (en) 2006-02-02 2016-09-13 The Board Of Trustees Of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
EP2385143A2 (en) 2006-02-02 2011-11-09 The Board of Trustees of the Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US8008018B2 (en) 2006-02-02 2011-08-30 The Board Of Trustees Of The Leland Stanford Junior University Determination of fetal aneuploidies by massively parallel DNA sequencing
US10072295B2 (en) 2006-02-02 2018-09-11 The Board Of Trustees Of The Leland Stanford Junior University Non-invasive fetal genetic screening by digtal analysis
EP3002339A1 (en) 2006-02-02 2016-04-06 The Board of Trustees of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US9777329B2 (en) 2006-02-02 2017-10-03 The Board Of Trustees Of The Leland Stanford Junior University Non-invasive fetal genetic screening by digital analysis
US8609338B2 (en) 2006-02-28 2013-12-17 University Of Louisville Research Foundation, Inc. Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US20080020390A1 (en) * 2006-02-28 2008-01-24 Mitchell Aoy T Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US20110059451A1 (en) * 2006-02-28 2011-03-10 University Of Louisville Research Foundation Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US8663921B2 (en) 2006-02-28 2014-03-04 University Of Louisville Research Foundation, Inc. Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US8399195B2 (en) 2006-02-28 2013-03-19 University Of Louisville Research Foundation, Inc. Detecting genetic abnormalities
US10081841B2 (en) 2006-02-28 2018-09-25 University Of Louisville Research Foundation, Inc. Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US7799531B2 (en) 2006-02-28 2010-09-21 University Of Louisville Research Foundation Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms
US20110117548A1 (en) * 2006-02-28 2011-05-19 University Of Louisville Research Foundation, Inc. Detecting Fetal Chromosomal Abnormalities Using Tandem Single Nucleotide Polymorphisms
US20100184043A1 (en) * 2006-02-28 2010-07-22 University Of Louisville Research Foundation Detecting Genetic Abnormalities
US20100184044A1 (en) * 2006-02-28 2010-07-22 University Of Louisville Research Foundation Detecting Genetic Abnormalities
US20090203002A1 (en) * 2006-03-06 2009-08-13 Columbia University Mesenchymal stem cells as a vehicle for ion channel transfer in syncytial structures
EP3260556A1 (en) 2006-05-31 2017-12-27 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
EP2602321A1 (en) 2006-05-31 2013-06-12 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
US8679741B2 (en) 2006-05-31 2014-03-25 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
WO2007140417A2 (en) 2006-05-31 2007-12-06 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
US9453257B2 (en) 2006-05-31 2016-09-27 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
US20100297710A1 (en) * 2006-05-31 2010-11-25 Sequenom, Inc. Methods and compositions for the extraction and amplification of nucleic acid from a sample
US20080070792A1 (en) * 2006-06-14 2008-03-20 Roland Stoughton Use of highly parallel snp genotyping for fetal diagnosis
US20080220422A1 (en) * 2006-06-14 2008-09-11 Daniel Shoemaker Rare cell analysis using sample splitting and dna tags
US9273355B2 (en) 2006-06-14 2016-03-01 The General Hospital Corporation Rare cell analysis using sample splitting and DNA tags
US8372584B2 (en) 2006-06-14 2013-02-12 The General Hospital Corporation Rare cell analysis using sample splitting and DNA tags
US8137912B2 (en) 2006-06-14 2012-03-20 The General Hospital Corporation Methods for the diagnosis of fetal abnormalities
US8168389B2 (en) 2006-06-14 2012-05-01 The General Hospital Corporation Fetal cell analysis using sample splitting
US9017942B2 (en) 2006-06-14 2015-04-28 The General Hospital Corporation Rare cell analysis using sample splitting and DNA tags
US9347100B2 (en) 2006-06-14 2016-05-24 Gpb Scientific, Llc Rare cell analysis using sample splitting and DNA tags
US20080096766A1 (en) * 2006-06-16 2008-04-24 Sequenom, Inc. Methods and compositions for the amplification, detection and quantification of nucleic acid from a sample
US20100261188A1 (en) * 2006-12-07 2010-10-14 Biocept, Inc. Non-invasive prenatal genetic screen
US8652780B2 (en) 2007-03-26 2014-02-18 Sequenom, Inc. Restriction endonuclease enhanced polymorphic sequence detection
US9051616B2 (en) 2007-07-23 2015-06-09 The Chinese University Of Hong Kong Diagnosing fetal chromosomal aneuploidy using massively parallel genomic sequencing
US20090029377A1 (en) * 2007-07-23 2009-01-29 The Chinese University Of Hong Kong Diagnosing fetal chromosomal aneuploidy using massively parallel genomic sequencing
US9121069B2 (en) 2007-07-23 2015-09-01 The Chinese University Of Hong Kong Diagnosing cancer using genomic sequencing
US8972202B2 (en) 2007-07-23 2015-03-03 The Chinese University Of Hong Kong Diagnosing fetal chromosomal aneuploidy using massively parallel genomic sequencing
US20100112590A1 (en) * 2007-07-23 2010-05-06 The Chinese University Of Hong Kong Diagnosing Fetal Chromosomal Aneuploidy Using Genomic Sequencing With Enrichment
US8442774B2 (en) 2007-07-23 2013-05-14 The Chinese University Of Hong Kong Diagnosing fetal chromosomal aneuploidy using paired end
US8852416B2 (en) 2008-02-01 2014-10-07 The University Of British Columbia Methods and apparatus for particle introduction and recovery
US20110033862A1 (en) * 2008-02-19 2011-02-10 Gene Security Network, Inc. Methods for cell genotyping
US8709726B2 (en) 2008-03-11 2014-04-29 Sequenom, Inc. Nucleic acid-based tests for prenatal gender determination
US20090317817A1 (en) * 2008-03-11 2009-12-24 Sequenom, Inc. Nucleic acid-based tests for prenatal gender determination
US8722336B2 (en) 2008-03-26 2014-05-13 Sequenom, Inc. Restriction endonuclease enhanced polymorphic sequence detection
US20110092763A1 (en) * 2008-05-27 2011-04-21 Gene Security Network, Inc. Methods for Embryo Characterization and Comparison
US20110130558A1 (en) * 2008-05-30 2011-06-02 Qiagen Gmbh Method for isolating nucleic acids
US9790250B2 (en) 2008-05-30 2017-10-17 Qiagen Gmbh Method for isolating short-chain nucleic acids
US9809612B2 (en) * 2008-05-30 2017-11-07 Qiagen Gmbh Method for isolating nucleic acids
US20110160446A1 (en) * 2008-05-30 2011-06-30 Qiagen Gmbh Method for isolating short-chain nucleic acids
US9639657B2 (en) 2008-08-04 2017-05-02 Natera, Inc. Methods for allele calling and ploidy calling
US20110178719A1 (en) * 2008-08-04 2011-07-21 Gene Security Network, Inc. Methods for Allele Calling and Ploidy Calling
US8962247B2 (en) 2008-09-16 2015-02-24 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses
US8476013B2 (en) 2008-09-16 2013-07-02 Sequenom, Inc. Processes and compositions for methylation-based acid enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses
EP3103871A1 (en) 2008-09-16 2016-12-14 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnostic
US8195415B2 (en) 2008-09-20 2012-06-05 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuploidy by sequencing
US9404157B2 (en) 2008-09-20 2016-08-02 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuploidy by sequencing
US8296076B2 (en) 2008-09-20 2012-10-23 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuoploidy by sequencing
US8682594B2 (en) 2008-09-20 2014-03-25 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuploidy by sequencing
US9353414B2 (en) 2008-09-20 2016-05-31 The Board Of Trustees Of The Leland Stanford Junior University Noninvasive diagnosis of fetal aneuploidy by sequencing
US9850480B2 (en) 2009-04-03 2017-12-26 Sequenom, Inc. Nucleic acid preparation compositions and methods
US10053685B2 (en) 2009-04-03 2018-08-21 Sequenom, Inc. Nucleic acid preparation compositions and methods
US8771948B2 (en) 2009-04-03 2014-07-08 Sequenom, Inc. Nucleic acid preparation compositions and methods
US9580741B2 (en) 2009-04-03 2017-02-28 Sequenom, Inc. Nucleic acid preparation compositions and methods
US8877028B2 (en) 2009-04-21 2014-11-04 The University Of British Columbia System and methods for detection of particles
WO2011034631A1 (en) 2009-09-16 2011-03-24 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non invasive prenatal diagnoses
EP3330382A1 (en) 2009-09-16 2018-06-06 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses
US9228234B2 (en) 2009-09-30 2016-01-05 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US10061890B2 (en) 2009-09-30 2018-08-28 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US10061889B2 (en) 2009-09-30 2018-08-28 Natera, Inc. Methods for non-invasive prenatal ploidy calling
EP3241914A1 (en) 2009-11-05 2017-11-08 The Chinese University Of Hong Kong Fetal genomic analysis from a maternal biological sample
US10093976B2 (en) 2009-11-05 2018-10-09 The Chinese University Of Hong Kong Identifying a de novo fetal mutation from a maternal biological sample
WO2011057094A1 (en) 2009-11-05 2011-05-12 The Chinese University Of Hong Kong Fetal genomic analysis from a maternal biological sample
US9512480B2 (en) 2009-11-05 2016-12-06 The Chinese University Of Hong Kong Determination of the depth coverage of the fetal genome
US20110105353A1 (en) * 2009-11-05 2011-05-05 The Chinese University of Hong Kong c/o Technology Licensing Office Fetal Genomic Analysis From A Maternal Biological Sample
US8467976B2 (en) 2009-11-05 2013-06-18 The Chinese University Of Hong Kong Fetal genomic analysis from a maternal biological sample
US8620593B2 (en) 2009-11-06 2013-12-31 The Chinese University Of Hong Kong Size-based genomic analysis
WO2011054936A1 (en) 2009-11-06 2011-05-12 The Chinese University Of Hong Kong Size-based genomic analysis
US9982300B2 (en) 2009-11-06 2018-05-29 The Chinese University Of Hong Kong Size-based genomic analysis
US9926593B2 (en) 2009-12-22 2018-03-27 Sequenom, Inc. Processes and kits for identifying aneuploidy
US8426122B2 (en) 2010-03-11 2013-04-23 Cellscape Corporation Method and device for identification of nucleated red blood cells from a maternal blood sample
US8774488B2 (en) 2010-03-11 2014-07-08 Cellscape Corporation Method and device for identification of nucleated red blood cells from a maternal blood sample
US10017812B2 (en) 2010-05-18 2018-07-10 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US9334541B2 (en) 2010-05-18 2016-05-10 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US9163282B2 (en) 2010-05-18 2015-10-20 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US8825412B2 (en) 2010-05-18 2014-09-02 Natera, Inc. Methods for non-invasive prenatal ploidy calling
US10113196B2 (en) 2010-05-18 2018-10-30 Natera, Inc. Prenatal paternity testing using maternal blood, free floating fetal DNA and SNP genotyping
US8949036B2 (en) 2010-05-18 2015-02-03 Natera, Inc. Methods for non-invasive prenatal ploidy calling
WO2011156387A2 (en) 2010-06-07 2011-12-15 Esoterix Genetic Laboratories, Llc Enumeration of nucleic acids
WO2012114075A1 (en) 2011-02-25 2012-08-30 University Of Plymouth Method for processing maternal and fetal dna
US8450061B2 (en) 2011-04-29 2013-05-28 Sequenom, Inc. Quantification of a minority nucleic acid species
US8460872B2 (en) 2011-04-29 2013-06-11 Sequenom, Inc. Quantification of a minority nucleic acid species
US8455221B2 (en) 2011-04-29 2013-06-04 Sequenom, Inc. Quantification of a minority nucleic acid species
US9434938B2 (en) 2011-05-20 2016-09-06 The University Of British Columbia Systems and methods for enhanced SCODA
US8518228B2 (en) 2011-05-20 2013-08-27 The University Of British Columbia Systems and methods for enhanced SCODA
US9547748B2 (en) 2011-06-29 2017-01-17 Bgi Health Service Co., Ltd. Method for determining fetal chromosomal abnormality
US9984198B2 (en) 2011-10-06 2018-05-29 Sequenom, Inc. Reducing sequence read count error in assessment of complex genetic variations
US9367663B2 (en) 2011-10-06 2016-06-14 Sequenom, Inc. Methods and processes for non-invasive assessment of genetic variations
WO2013075100A1 (en) * 2011-11-17 2013-05-23 Cellscape Corporation Methods, devices, and kits for obtaining and analyzing cells
US9186685B2 (en) 2012-01-13 2015-11-17 The University Of British Columbia Multiple arm apparatus and methods for separation of particles
US9555354B2 (en) 2012-01-13 2017-01-31 The University Of British Columbia Multiple arm apparatus and methods for separation of particles
US9605313B2 (en) 2012-03-02 2017-03-28 Sequenom, Inc. Methods and processes for non-invasive assessment of genetic variations
US9892230B2 (en) 2012-03-08 2018-02-13 The Chinese University Of Hong Kong Size-based analysis of fetal or tumor DNA fraction in plasma
US9512477B2 (en) 2012-05-04 2016-12-06 Boreal Genomics Inc. Biomarker anaylsis using scodaphoresis
US9840732B2 (en) 2012-05-21 2017-12-12 Fluidigm Corporation Single-particle analysis of particle populations
US9920361B2 (en) 2012-05-21 2018-03-20 Sequenom, Inc. Methods and compositions for analyzing nucleic acid
WO2014011928A1 (en) 2012-07-13 2014-01-16 Sequenom, Inc. Processes and compositions for methylation-based enrichment of fetal nucleic acid from a maternal sample useful for non-invasive prenatal diagnoses
US9598731B2 (en) 2012-09-04 2017-03-21 Guardant Health, Inc. Systems and methods to detect rare mutations and copy number variation
US10041127B2 (en) 2012-09-04 2018-08-07 Guardant Health, Inc. Systems and methods to detect rare mutations and copy number variation
US9902992B2 (en) 2012-09-04 2018-02-27 Guardant Helath, Inc. Systems and methods to detect rare mutations and copy number variation
US9840743B2 (en) 2012-09-04 2017-12-12 Guardant Health, Inc. Systems and methods to detect rare mutations and copy number variation
US9834822B2 (en) 2012-09-04 2017-12-05 Guardant Health, Inc. Systems and methods to detect rare mutations and copy number variation
US9340835B2 (en) 2013-03-15 2016-05-17 Boreal Genomics Corp. Method for separating homoduplexed and heteroduplexed nucleic acids
US10106836B2 (en) 2013-03-15 2018-10-23 The Chinese University Of Hong Kong Determining fetal genomes for multiple fetus pregnancies
US9499870B2 (en) 2013-09-27 2016-11-22 Natera, Inc. Cell free DNA diagnostic testing standards
US9920366B2 (en) 2013-12-28 2018-03-20 Guardant Health, Inc. Methods and systems for detecting genetic variants
US9677118B2 (en) 2014-04-21 2017-06-13 Natera, Inc. Methods for simultaneous amplification of target loci
US10011870B2 (en) 2016-12-07 2018-07-03 Natera, Inc. Compositions and methods for identifying nucleic acid molecules

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