Diagnosing fetal chromosomal aneuploidy using paired end
First Claim
1. A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a fetus by analyzing a biological sample obtained from a female subject pregnant with the fetus, wherein the biological sample includes nucleic acid molecules from the female subject and from the fetus, the method comprising:
- sequencing a plurality of the nucleic acid molecules contained in the biological sample to obtain paired-end sequence reads for each of the plurality of nucleic acid molecule;
aligning the paired-end sequenced reads of the plurality of nucleic acid molecules to identify from which chromosomes the nucleic acid molecules originate;
determining a length for each of the plurality of nucleic acid molecules based on the paired-end sequence reads;
determining a first amount of nucleic acid molecules identified as originating from a first chromosome;
determining a second amount of nucleic acid molecules identified as originating from one or more second chromosomes, wherein the determination of the first amount and the second amount is based on the determined lengths of the corresponding nucleic acid molecules;
determining a parameter from the first amount and the second amount;
comparing the parameter to one or more cutoff values; and
based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome.
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Abstract
Embodiments of this invention provide methods, systems, and apparatus for determining whether a fetal chromosomal aneuploidy exists from a biological sample obtained from a pregnant female. Nucleic acid molecules of the biological sample are sequenced, such that a fraction of the genome is sequenced. Respective amounts of a clinically-relevant chromosome and of background chromosomes are determined from results of the sequencing. The determination of the relative amounts may count sequences of only certain length. A parameter derived from these amounts (e.g. a ratio) is compared to one or more cutoff values, thereby determining a classification of whether a fetal chromosomal aneuploidy exists. Prior to sequencing, the biological sample may be enriched for DNA fragments of a particular sizes.
90 Citations
21 Claims
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1. A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a fetus by analyzing a biological sample obtained from a female subject pregnant with the fetus, wherein the biological sample includes nucleic acid molecules from the female subject and from the fetus, the method comprising:
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sequencing a plurality of the nucleic acid molecules contained in the biological sample to obtain paired-end sequence reads for each of the plurality of nucleic acid molecule; aligning the paired-end sequenced reads of the plurality of nucleic acid molecules to identify from which chromosomes the nucleic acid molecules originate; determining a length for each of the plurality of nucleic acid molecules based on the paired-end sequence reads; determining a first amount of nucleic acid molecules identified as originating from a first chromosome; determining a second amount of nucleic acid molecules identified as originating from one or more second chromosomes, wherein the determination of the first amount and the second amount is based on the determined lengths of the corresponding nucleic acid molecules; determining a parameter from the first amount and the second amount; comparing the parameter to one or more cutoff values; and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21)
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20. A computer program product comprising a computer readable medium encoded with a plurality of instructions for controlling a computing system to perform an operation for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a fetus by analyzing a biological sample obtained from a female subject pregnant with the fetus, wherein the biological sample includes nucleic acid molecules from the female subject and from the fetus, the operation comprising:
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receiving paired-end sequence reads for each of a plurality of the nucleic acid molecules contained in the biological sample; aligning the paired-end sequenced reads of the plurality of nucleic acid molecules to identify from which chromosomes the nucleic acid molecules originate; determining a length for each of the plurality of nucleic acid molecules based on the paired-end sequence reads; determining a first amount of nucleic acid molecules identified as originating from a first chromosome; determining a second amount of nucleic acid molecules identified as originating from one or more of the second chromosomes, wherein the determination of the first amount and the second amount is based on the determined lengths of the corresponding nucleic acid molecules; determining a parameter from the first amount and the second amount; comparing the parameter to one or more cutoff values; and based on the comparison, determining a classification of whether a fetal chromosomal aneuploidy exists for the first chromosome.
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Specification