# US 2018/0025109 A1 · Methods for non-invasive prenatal ploidy calling

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- Number: US 2018/0025109 A1
- Document ID: US20180025109A1
- Status: Published application
- Kind: A1
- Application number: 15/727,428
- Filed: 2017-10-06
- Published: 2018-01-25
- Earliest claimed: 2010-05-18
- Assignees: Natera, Inc.
- Applicants: Natera, Inc.
- Inventors: Matthew Rabinowitz; George Gemelos; Milena Banjevic; Allison Ryan; Zachary Demko; Matthew Hill; Bernhard Zimmermann; Johan Baner
- Web page: https://patentgrep.com/patent/US20180025109A1

## CPC

- G16B 20/00: ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- C12Q 1/6806: Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay (C12Q1/6804 takes precedence)
- C12Q 1/6827: for detection of mutation or polymorphism
- C12Q 1/686: Polymerase chain reaction [PCR]
- C12Q 1/6862: Ligase chain reaction [LCR]
- C12Q 1/6869: Methods for sequencing
- C12Q 1/6874: involving nucleic acid arrays, e.g. sequencing by hybridisation
- C12Q 1/6883: for diseases caused by alterations of genetic material
- G16B 20/10: Ploidy or copy number detection
- G16B 20/20: Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
- G16B 20/40: Population genetics; Linkage disequilibrium
- C12Q 2525/179: incorporating arbitrary or random nucleotide sequences
- C12Q 2527/113: Time
- C12Q 2527/143: Concentration of primer or probe
- C12Q 2537/143: Multiplexing, i.e. use of multiple primers or probes in a single reaction, usually for simultaneously analyse of multiple analysis
- C12Q 2537/149: Sequential reactions
- C12Q 2537/159: Reduction of complexity, e.g. amplification of subsets, removing duplicated genomic regions
- C12Q 2545/114: involving a quantitation step
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/16: Primer sets for multiplex assays
- G16B 40/00: ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## 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.

## Claims

### Claim 1

A method for determining whether one or more mutations are present in free floating DNA in a maternal blood sample, comprising:
(i) isolating free floating DNA from the maternal blood sample,
(ii) performing PCR to amplify the isolated DNA,
(iii) performing hybrid capture using hybrid capture probes directed to genetic loci associated with one or more diseases or genetic states of interest to enrich the amplified DNA,
(iv) performing PCR to amplify the enriched DNA,
(v) performing high throughput DNA sequencing to generate nucleic acid sequence data for the amplified enriched DNA, and
(vi) determining from the sequence data whether the one or more mutations are present in the DNA.

### Claim 2

A method for sequencing DNA derived from a maternal blood sample, comprising:
(i) isolating free floating DNA from a maternal blood sample,
(ii) performing PCR to amplify the isolated DNA,
(iii) performing hybrid capture using hybrid capture probes directed to genetic loci associated with one or more diseases or genetic states of interest to enrich the amplified DNA,
(iv) performing PCR to amplify the enriched DNA, and
(v) performing high throughput DNA sequencing to sequence the amplified enriched DNA.