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Methods and processes for non-invasive assessment of genetic variations

  • US 10,497,461 B2
  • Filed: 03/12/2013
  • Issued: 12/03/2019
  • Est. Priority Date: 06/22/2012
  • Status: Active Grant
First Claim
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1. A computer-implemented method for sequencing test sample nucleic acid from a pregnant female, generating a classification of presence of a sex chromosome aneuploidy for the test sample nucleic acid, and performing a medical procedure comprising amniocentesis or chorionic villus sampling, comprising:

  • (a) isolating circulating cell-free nucleic acid from blood of the pregnant female bearing a fetus;

    (b) sequencing the test sample nucleic acid by a genome-wide massively parallel sequencer that generates sequence reads, which test sample nucleic acid comprises the isolated circulating cell-free nucleic acid;

    (c) mapping, using a microprocessor, the sequence reads to portions of a reference genome;

    (d) counting the sequence reads mapped to the portions, which counting generates counts of sequence reads mapped to the portions;

    (e) calculating, using a microprocessor, a guanine and cytosine (GC) bias coefficient for the test sample nucleic acid based on a fitted relation between (i) the counts of the sequence reads mapped to each of the portions and (ii) GC content for each of the portions, wherein the GC bias coefficient is a slope for a fitted linear relation or a curvature estimation for a non-linear fitted relation;

    (f) calculating, using a microprocessor, a genomic section level for each of the portions based on the counts of (d), the GC bias coefficient of (e) and a fitted relation, for each of the portions, between (i) the GC bias coefficient for each of multiple samples and (ii) the counts of the sequence reads mapped to each of the portions for the multiple samples, which calculating generates normalized genomic section levels;

    (g) calculating, using a microprocessor, a Z-score from the normalized genomic section levels;

    (h) generating, using a microprocessor, the classification of the presence of the sex chromosome aneuploidy for the test sample nucleic acid according to the Z-score calculated in (g); and

    (i) performing a medical procedure comprising amniocentesis or chorionic villus sampling for the pregnant female after (h).

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