Detecting fetal chromosomal abnormalities using tandem single nucleotide polymorphisms

1. A method for determining whether a fetus has a trisomy, said method comprising:

obtaining fetal and maternal cell-free DNA from maternal blood;

using a computer implementation of a mathematical algorithm, designing primers to amplify target sequences comprising tandem SNPs on selected chromosomes in the fetal and maternal cell-free DNA;

using the designed primers, amplifying the target sequences comprising tandem SNPs to produce amplicons from the cell-free DNA from maternal blood;

sequencing the amplicons using high-throughput sequencing;

identifying the tandem SNPs by comparing the sequenced amplicons to a reference sequence;

determining heterozygosity of the tandem SNPs for each of the selected chromosomes;

identifying target sequences exhibiting three haploytpes of at least one tandem SNP, wherein at least one of said haplotypes is not present in the maternal DNA;

comparing the three haplotypes by determining the relative copy number of each of the haplotypes; and

determining that the fetus has a trisomy based on the relative copy number of the three haplotypes.

2. The method of claim 1 , wherein the amplification is accomplished by high-fidelity PCR.

3. The method of claim 1 , wherein the high-throughput sequencing is at a single molecule level.

4. The method of claim 1 , wherein comparing the sequenced amplicons requires a substantial identity between the amplicons of at least 95%.

5. The method of claim 1 , wherein comparing the sequenced amplicons requires a substantial identity between the amplicons of at least 98%.

6. The method of claim 1 , wherein comparing the sequenced amplicons requires a substantial identity between the amplicons of at least 99%.