# US 10,767,228 B2 · Fetal chromosomal aneuploidy diagnosis

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- Number: US 10,767,228 B2
- Document ID: US10767228B2
- Status: Granted
- Kind: B2
- Application number: 15/985,092
- Filed: 2018-05-21
- Published: 2018-12-20
- Granted: 2020-09-08
- Earliest claimed: 2011-10-18
- Assignees: Multiplicom NV
- Applicants: Multiplicom NV
- Inventors: Jurgen Del-Favero; Dirk Goossens; Lien Heyrman
- Web page: https://patentgrep.com/patent/US10767228B2

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 1/686: Polymerase chain reaction [PCR]
- C12Q 1/6869: Methods for sequencing
- G16B 25/00: ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B 25/20: Polymerase chain reaction [PCR]; Primer or probe design; Probe optimisation
- 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
- G16H 50/20: for computer-aided diagnosis, e.g. based on medical expert systems
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/16: Primer sets for multiplex assays
- 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
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA

## Abstract

The invention relates to prenatal detection methods using non-invasive techniques. In particular, it relates to prenatal diagnosis of a fetal chromosomal aneuploidy by detecting fetal and maternal nucleic acids in a maternal biological sample. More particularly, the invention applies multiplex PCR to amplify selected fractions of the respective chromosomes of maternal and fetal chromosomes. Respective amounts of suspected aneuploid chromosomal regions and reference chromosomes are determined from massive sequencing analysis followed by a statistical analysis to detect a particular aneuploidy.

## Claims

### Claim 1

A method for analyzing DNA sequencing reads, comprising
sequencing amplified target DNA sequences from at least one quantitative multiplex PCR reaction, wherein the amplified target DNA sequences are from a biological sample of a pregnant female and comprise one or more chromosomal regions suspected of being aneuploidy and one or more chromosomal regions of a reference chromosome; and
calculating the sum of read counts for all amplified target DNA sequences of the suspected chromosomal aneuploidy followed by normalization, against the sum of read counts for all amplified DNA sequences of the reference chromosome to determine by statistical methods a set score indicative for the presence of a fetal chromosomal aneuploidy.

### Claim 2 (depends on 1)

The method of claim 1, wherein said fetal chromosomal aneuploidy is chromosome 13 and/or chromosome 18 and/or chromosome 21 and/or chromosome X and/or chromosome Y.

### Claim 3 (depends on 1)

The method of claim 1, wherein said biological sample is maternal blood, plasma, urine, cerebrospinal fluid, serum, saliva or is transcervical lavage fluid.

### Claim 4 (depends on 1)

The method of claim 1, wherein the amplified target DNA sequences have a size between 30-180 base pairs.

### Claim 5 (depends on 1)

The method of claim 1, wherein the GC content of the amplified target DNA sequences is between 20 and 70%.

### Claim 6 (depends on 1)

The method of claim 1, wherein the amplified target DNA sequences are obtained in a single multiplex PCR reaction.

### Claim 7 (depends on 6)

The method of claim 6, wherein in said single multiplex PCR reaction more than 40 amplified DNA sequences are obtained.

### Claim 8 (depends on 6)

The method of claim 6, wherein in said single multiplex PCR reaction more than 60 amplified DNA sequences are obtained.