Diagnosing Fetal Chromosomal Aneuploidy Using Genomic Sequencing With Enrichment
First Claim
1. A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the method comprising:
- receiving the biological sample;
sequencing at least a portion of a plurality of the nucleic acid molecules contained in the biological sample, wherein the sequenced portion of each nucleic acid molecule includes both ends of the respective nucleic acid molecule;
based on the sequencing;
determining a length for each of the portion of nucleic acid molecules;
determining a first amount of a first chromosome from sequences identified as originating from the first chromosome; and
determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes, wherein the determination of the first amount and the second amount includes counting sequences based on the 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.
273 Citations
25 Claims
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1. A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the method comprising:
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receiving the biological sample; sequencing at least a portion of a plurality of the nucleic acid molecules contained in the biological sample, wherein the sequenced portion of each nucleic acid molecule includes both ends of the respective nucleic acid molecule; based on the sequencing; determining a length for each of the portion of nucleic acid molecules; determining a first amount of a first chromosome from sequences identified as originating from the first chromosome; and determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes, wherein the determination of the first amount and the second amount includes counting sequences based on the 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)
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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 biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the operation comprising:
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receiving the biological sample; sequencing at least a portion of a plurality of the nucleic acid molecules contained in the biological sample, wherein the sequenced portion of each nucleic acid molecule includes both ends of the respective nucleic acid molecule; based on the sequencing; determining a length for each of the portion of nucleic acid molecules; determining a first amount of a first chromosome from sequences identified as originating from the first chromosome; and determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes, wherein the determination of the first amount and the second amount includes counting sequences based on the 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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21. A method for performing prenatal diagnosis of a fetal chromosomal aneuploidy in a biological sample obtained from a pregnant female subject, wherein the biological sample includes nucleic acid molecules, the method comprising:
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receiving the biological sample; sequencing at least a portion of a plurality of the nucleic acid molecules contained in the biological sample, wherein the biological sample has been enriched for sequences less than a first predetermined number of nucleotides, wherein the first predetermined number is between about 125 and about 175 nucleotides; based on the sequencing; determining a first amount of a first chromosome from sequences identified as originating from the first chromosome; and determining a second amount of one or more second chromosomes from sequences identified as originating from one of the second chromosomes; 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 (22, 23, 24, 25)
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Specification