Methods for non-invasive prenatal ploidy calling
First Claim
1. A method of detecting a trisomy of at least one chromosome or chromosome segment of interest in the genome of a fetus, the method comprising:
- performing a multiplex amplification to amplify at least 1,000 polymorphic loci from free floating maternal and fetal DNA in a maternal blood, plasma, or serum sample using a plurality of primers in one reaction mixture to obtain amplified products, wherein the polymorphic loci comprise single nucleotide polymorphisms (SNPs);
obtaining genetic data from amplified products;
generating a set of one or more hypotheses specifying the number of copies of one or more of the chromosomes or chromosome segments of interest present in the genome of the fetus;
wherein one of the hypotheses specifies that one or more of the chromosomes or chromosome segments of interest are trisomic;
calculating expected genetic data of the fetus for each of the hypotheses;
determining the probability of the hypotheses according to a data fit between the obtained genetic data of the fetus and the expected genetic data of the fetus using a technique selected from the group consisting of maximum a- posteriori estimation and maximum likelihood estimation;
wherein the probability of the hypothesis is determined without genetic data from a reference chromosome; and
outputting the hypothesis with the greatest probability as an indication that there is a trisomy in the genome of the fetus.
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Abstract
The present disclosure provides methods for determining the ploidy status of a chromosome in a gestating fetus from genotypic data measured from a mixed sample of DNA comprising DNA from both the mother of the fetus and from the fetus, and optionally from genotypic data from the mother and father. The ploidy state is determined by using a joint distribution model to create a plurality of expected allele distributions for different possible fetal ploidy states given the parental genotypic data, and comparing the expected allelic distributions to the pattern of measured allelic distributions measured in the mixed sample, and choosing the ploidy state whose expected allelic distribution pattern most closely matches the observed allelic distribution pattern. The mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias, for example using massively multiplexed targeted PCR.
230 Citations
29 Claims
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1. A method of detecting a trisomy of at least one chromosome or chromosome segment of interest in the genome of a fetus, the method comprising:
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performing a multiplex amplification to amplify at least 1,000 polymorphic loci from free floating maternal and fetal DNA in a maternal blood, plasma, or serum sample using a plurality of primers in one reaction mixture to obtain amplified products, wherein the polymorphic loci comprise single nucleotide polymorphisms (SNPs); obtaining genetic data from amplified products; generating a set of one or more hypotheses specifying the number of copies of one or more of the chromosomes or chromosome segments of interest present in the genome of the fetus;
wherein one of the hypotheses specifies that one or more of the chromosomes or chromosome segments of interest are trisomic;calculating expected genetic data of the fetus for each of the hypotheses; determining the probability of the hypotheses according to a data fit between the obtained genetic data of the fetus and the expected genetic data of the fetus using a technique selected from the group consisting of maximum a- posteriori estimation and maximum likelihood estimation;
wherein the probability of the hypothesis is determined without genetic data from a reference chromosome; andoutputting the hypothesis with the greatest probability as an indication that there is a trisomy in the genome of the fetus. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A method for determining whether a fetus is triploid with trisomic autosomal chromosomes, the method comprising:
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performing a multiplex amplification to amplify at least 1,000 polymorphic loci from free floating maternal and fetal DNA in a material blood, plasma, or serum sample using a plurality of primers in one reaction mixture to obtain genetic data from amplified products, wherein the polymorphic loci comprise single nucleotide polymorphisms (SNPs); obtaining genetic data from amplified products calculating, expected genetic data of the fetus for a hypothesis in which the fetus is triploid; calculating, expected genetic data of the fetus for at least one hypothesis in which the fetus is not triploid; determining the probability of the hypotheses in which the fetus is triploid and the probability of the hypothesis in which the fetus is not triploid according to a data fit between the obtained genetic data of the fetus and the expected genetic data of the fetus using a technique selected from the group consisting of maximum a-posteriori estimation and maximum likelihood estimation;
wherein the probability of the hypothesis is determined without genetic data from a reference chromosome; andoutputting the hypothesis with the greatest probability as an indication of whether the fetus is triploid with trisomic autosomal chromosomes. - View Dependent Claims (22, 23, 24, 25, 26, 27, 28, 29)
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Specification