WO2014133369A1 - Méthode et appareil permettant de diagnostiquer l'aneuploïdie foetale par séquençage génomique - Google Patents

Méthode et appareil permettant de diagnostiquer l'aneuploïdie foetale par séquençage génomique Download PDF

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WO2014133369A1
WO2014133369A1 PCT/KR2014/001704 KR2014001704W WO2014133369A1 WO 2014133369 A1 WO2014133369 A1 WO 2014133369A1 KR 2014001704 W KR2014001704 W KR 2014001704W WO 2014133369 A1 WO2014133369 A1 WO 2014133369A1
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chromosome
score
analysis target
section
sequence
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Korean (ko)
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박종화
김태형
김종수
박신기
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주식회사 테라젠이텍스
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

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  • the present invention relates to a method for non-invasive fetal malformation prenatal diagnosis. More specifically, the present invention relates to a method and apparatus for diagnosing abnormality by analyzing sequencing information on genomic DNA extracted from mother's blood and accurately determining the fetal chromosome aneuploidy. will be.
  • Prenatal diagnosis' refers to the process of determining and diagnosing the disease of a fetus before the fetus is born. According to a recent domestic statistics, congenital malformations account for about 3% of all newborns, and about 20% of congenital malformations are due to chromosomal abnormalities. In particular, the well-known malformations of Down's syndrome account for about 26% of congenital malformations.
  • the interest in prenatal diagnosis is increasing day by day due to the increase in birth rate and development of various prenatal diagnosis equipment.
  • fetal malformations are suspected in maternal serum screening and ultrasonography.
  • Prenatal diagnosis can be divided into invasive and non-invasive diagnosis.
  • invasive diagnostics include chorionic villi sampling (CVS) performed between 10 and 12 weeks of gestation, and fetal chromosomes by measuring the concentration of AFP in amniotic fluid using immunoassay between 15 and 20 weeks of gestation. Amniocentesis to analyze, cordocentesis to extract fetal blood directly from the umbilical cord under ultrasound guidance between 18 and 20 weeks of gestation.
  • CVS chorionic villi sampling
  • fetal chromosomes by measuring the concentration of AFP in amniotic fluid using immunoassay between 15 and 20 weeks of gestation.
  • Amniocentesis to analyze cordocentesis to extract fetal blood directly from the umbilical cord under ultrasound guidance between 18 and 20 weeks of gestation.
  • invasive diagnostic methods such as the above may cause abortion, disease, or malformation by shocking the fetus during the examination, and non-invasive diagnostic methods have been developed
  • the pre-implantation genetic diagnosis method is a technique for selecting embryos without pre-implantation genetic defects using molecular genetic or cytogenetic techniques used in in vitro fertilization.
  • QF-PCR quantitative-fluorescent PCR
  • STRs short tandem repeats
  • DNA auto-sequence analyzer is a rapid screening test to measure the amount of fluorescence amplified DNA.
  • a chromosomal microarray (CMA) method and the like are known which accumulate and examine a mapped DNA sequence mapped on a glass slide in order to find a copy number change.
  • next-generation sequencing technologies are also used in the prenatal diagnosis area.
  • NGS next-generation sequencing
  • the mother's blood contains about 10% of the genome of the fetus
  • prenatal diagnostic methods are known to separate fetal cells from the mother's blood and analyze the chromosomes.
  • Korean Patent Application No. 2010-7003969 discloses a method for diagnosing fetal chromosome aberration using massively parallel genomic sequencing.
  • U.S. Patent No. 8195415 also discloses a method of quantitatively analyzing the mapping of DNA obtained from maternal blood for a specific length for each chromosome.
  • the present invention analyzes genomic DNA (genomic DNA) extracted from the blood of pregnant mothers of normal fetuses and chromosome aneuploids (Filter and Read Depth for the GC content) Filter) and Z-score CutOff values, and check the abnormality of Z-score values based on the Z-score CutOff values using the extracted parameters for the subjects to be diagnosed.
  • genomic DNA genomic DNA
  • chromosome aneuploids Feter and Read Depth for the GC content
  • Filter Z-score CutOff values
  • the 'section' may be set in units of 300kb on genomic DNA.
  • the step of removing a portion of low confidence in the sequence information from the analysis target a method for removing mismatch parts, the removal of the read (read) sequence parts attached to various sites Method, and methods for removing redundant reads from PCR.
  • the diagnostic method may be a method for diagnosing whether a fetus is at least one chromosome selected from the group consisting of chromosomes 13, 18 and 21 of the fetus.
  • the diagnostic method according to the present invention has the advantage of being easy to harm the mother or the fetus in that it can be analyzed using the mother's blood sample. It was also confirmed that even a small amount of fetal chromosome can make a very accurate diagnosis. Therefore, the method of the present invention can be usefully used as a prenatal diagnosis method that can determine whether the abnormality due to abnormalities in the fetal chromosome early.
  • FIG. 1 is a flow chart showing a diagnostic method of the present invention.
  • step 3 is a detailed flowchart of step 3) of a diagnostic method according to an embodiment of the present invention.
  • step 3 is a detailed flowchart of step 1) of a diagnostic method according to an embodiment of the present invention.
  • FIG. 4 is a plot illustrating the quality of base sequences and the distribution of the base sequences by type of data generated through sequencing.
  • Figure 5 shows the results of confirming the read thickness distribution (depth distribution) for genomic DNA set to 300kb intervals according to an embodiment of the present invention.
  • FIG. 6 is a result of analyzing the GC content.
  • the figure on the left shows the distribution on the entire DNA, and the figure on the right shows an enlarged portion of the high frequency (darker one). Dark areas are areas of high frequency.
  • FIG. 7 is a diagram showing a method for determining the feasibility of chromosomes 13, 18 and 21 of a fetus by the method of the present invention with respect to genomic DNA set to 300 kb in accordance with an embodiment of the present invention. .
  • FIG. 8 is a table showing the accuracy of the diagnostic method of the present invention.
  • the result of the karyotype analysis was compared with the results of fetuses diagnosed by chromosome 18 (4 in chromosome 18 and 7 in chromosome 21).
  • Four patients (100%) and seven (100%) of chromosome 21 were diagnosed as 74 (100%).
  • FIG. 9 is a block diagram of a diagnostic apparatus of the present invention.
  • the present invention relates to a method for diagnosing chromosomal aberration of a fetus by analyzing genomic DNA extracted from blood of pregnant mothers of a normal fetus.
  • the method of extracting genomic DNA (genomic DNA) from the blood sample of step 1) can be widely used known DNA extraction method.
  • a library is prepared for samples that have passed quality control standards through qualitative and quantitative analysis of samples.
  • the amplified adapter-ligated lirary is amplified, the amplified sample is purified, and tested using a Bioanalyzer.
  • the library that has passed the quality inspection creates an ISP using One-Touch2 device for template prep.
  • Once the ISP for sequencing has been made install the Sequencing 200kit V2 on Proton and load the ISP made on the PI chip. After placing the chip in the device, perform chip check to confirm that there is no problem with the chip and reagents, and proceed with sequencing. In the Monitor Tab of the Torrent Browser, check if Loading, Live ISPs, Library ISPs are normal.
  • Step 3) comprises: 3-1) checking whether the analysis target is determined for each section set for the sequence information, and removing the sequence section identified as an inappropriate sequence section from the analysis target; And 3-2) setting the portion corresponding to the reference range as an analysis target by examining the GC content of the remaining sequence section portion (FIG. 2).
  • Step 3-1) is a step of removing a portion of low reliability of the sequence information from the analysis target by checking the thickness distribution of the reads by a predetermined interval, but is not limited thereto.
  • the interval may be set in units of 300 kb.
  • the reason for setting the 300 kb as above is to filter by using a nucleotide sequence GC ratio. This is because it can form a group of ratios and is easy for statistical analysis.
  • the sequence section to be removed may include multiple overlapping sequences and PCR duplicated reads, and the reason for removing the multiple overlapping sequences may be a repetitive sequence region.
  • the reason for this is that the PCR duplication reads are removed, and the reason for the amplification process is necessary for sequencing.
  • the high repeat region has a higher depth than the point where it is 80 percentile (the portion where the order in ascending order of each value is 80% of the number of values) to remove the portion. We removed the higher values and, conversely, lower values below 20 percentile (the order in which each value is 20% of the number of values) in order to remove the portion where noise can occur.
  • the part without thickness is excluded from the analysis because most of the region is N region.
  • the step 3-2) by removing the remaining portion of the sequence section by examining the GC content a method for setting only the sequence section that satisfies the condition of 0.35 ⁇ GC content ⁇ 0.45 It can be performed as. Since the GC content of the human genome is known to be about 40%, only the sequence information close to the human GC content is analyzed to increase accuracy.
  • Step 4) is a step of setting the Z-score according to the following equation using the thickness value of the intervals set as the analysis targets for the entire autosome.
  • the Z-score value according to the present invention is a value using the mean and standard deviation of the lead thickness (depth) for each section calculated for the entire autosomal body. In other words, we created a Z-score population with a standard deviation of 1 and a mean of 0 over the whole range. Therefore, all values are standardized.
  • the diagnostic method according to the present invention can diagnose whether a fetus is at least one chromosome selected from the group consisting of chromosomes 13, 18 and 21 of the fetus.
  • Chromosome abnormality 13 is associated with Patau syndrome. Patau syndrome occurs in 1 out of 25,000 to 25,000 fetuses, and is known to die within one year due to severe congenital malformations of important organs such as the central nervous system and heart.
  • Chromosome abnormality 18 is associated with Edwards syndrome. Edwards syndrome occurs in about 1 in every 8,000 fetuses and occurs three to four times more frequently in girls. Severe malformations and mental retardation of many organs are known to die within 10 weeks.
  • Chromosome abnormality 21 is associated with Down syndrome. It appears in 1 out of 800 people and shows symptoms such as mental retardation, physical deformity and growth disorder. Life span is between 20 and 30 years old.
  • step 6) is a step of determining whether the chromosomal abnormality by the average Z-score calculated for each chromosome, two groups (normal group, chromosomal abnormal group) that can not be assumed to follow the normal distribution Since we cannot compare the difference in size through the mean, we analyzed the Mann-Whitney test, a nonparametric method that does not characterize the parameters. The Z-score cutoff set to the difference between the lowest Z-score values was applied to determine the chromosomal abnormality when the cutoff value was exceeded.
  • FIG. 4 is a plot showing the quality of base sequences and distribution of base sequences for data generated through sequencing in an embodiment of the present invention.
  • Table 1 shows the results of nucleotide sequence decoded nucleotide sequences for each decoded sample, which produced 7,478,574 Read on average, and the average total number of produced sequences was 961,605,947 bp and the average total number of mapped sequences was 7,417,179 Read, which is 99.18%.
  • the amount produced in proportion to the number of base sequences of the reference sequence produced an average of 0.32X base sequences for each sample, assuming that the number of base sequences of the reference sequence was 1X.
  • the thickness of the read is extracted with a slide window of 500 bp for each 300 kb section, and the thickness distribution on the genome is confirmed by a line plot (FIG. 5). ).
  • the GC content was calculated using a human reference sequence and represented by a Scatter plot (FIG. 6). 6, the darker the color, the higher the frequency corresponding to the portion. Since the average human is known to have a GC content of 40%, the analysis of the present invention was performed by selecting regions having a GC content of 35 to 45%.
  • the high repeat region has a high depth so that the point where 80 percentile (the order in which each value is in the ascending order is 80% of the number of values) is removed to remove the portion. We removed the higher values, and conversely, lower than 20 percentile (in which the order in ascending order of each value is 20% of the number of each value) to remove the parts that may cause noise for the analysis. Values were removed.
  • the average value and standard deviation of the whole autosome were obtained by using the thickness of each section set to 300kb, and then Z-score group was created with the average of 0 and the standard deviation of 1, and for each chromosome.
  • the average value of Z-score was obtained and used for diagnosis (FIG. 7). In FIG.
  • the diagnostic method of the present invention is a method that can determine chromosomal abnormality relatively accurately even when the thickness (depth) of the chromosome analysis result is low. This confirmed that the prenatal diagnosis related to the number of fetal chromosomes is possible through the method of the present invention.
  • the mapping unit 20 for mapping the read sequences to the human reference genome, the thickness distribution of the read sequences, and the GC content are identified for each interval and set as an analysis target.
  • Analysis target setting unit 30, Z-score calculation unit 40 for calculating a Z-score value by using the depth value of the section set as the analysis target, each chromosome for the calculated Z-scores
  • the average value calculation unit 50 for calculating the average value for each and a Z-score average value calculated for each chromosome includes a determination unit 60 for determining whether the chromosomal abnormality.

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Abstract

L'invention concerne une méthode non invasive de diagnostic prénatal d'une malformation foetale. L'invention concerne plus particulièrement une méthode permettant de diagnostiquer s'il existe une anomalie, par obtention de paramètres issus de l'analyse des informations de séquençage de l'ADN génomique prélevé du sang d'une femme enceinte, et par détermination précise de l'aneuploïdie foetale. La méthode selon l'invention ne cause de tort ni à la femme enceinte ni au foetus et elle est simple à mettre en oeuvre étant donné qu'elle consiste en un simple prélèvement sanguin réalisé sur la femme enceinte. En outre, il a été confirmé qu'il était possible de réaliser une analyse très précise avec une petite quantité de chromosome foetal. La méthode selon l'invention peut donc être utile comme méthode de diagnostic prénatal permettant de déterminer précocement la présence d'une anomalie chromosomique foetale de nombre.
PCT/KR2014/001704 2013-02-28 2014-02-28 Méthode et appareil permettant de diagnostiquer l'aneuploïdie foetale par séquençage génomique WO2014133369A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN109988833A (zh) * 2017-12-29 2019-07-09 南京格致基因生物科技有限公司 宫颈癌的判断方法及系统
WO2020226528A1 (fr) * 2019-05-08 2020-11-12 Общество с ограниченной ответственностью "ГЕНОТЕК ИТ" Procédé pour déterminer le caryotype foetal chez une femme enceinte

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KR101817785B1 (ko) 2015-08-06 2018-01-11 이원다이애그노믹스(주) 다양한 플랫폼에서 태아의 성별과 성염색체 이상을 구분할 수 있는 새로운 방법
KR101678962B1 (ko) * 2015-08-21 2016-12-06 이승재 대규모 병렬형 게놈서열분석 방법을 이용한 비침습적 산전검사 장치 및 방법
WO2017051996A1 (fr) * 2015-09-24 2017-03-30 에스케이텔레콤 주식회사 Procédé de détermination d'aneuploïdie chromosomique fœtale de type non invasif
KR101678959B1 (ko) 2015-12-08 2016-11-23 왕선주 태아의 유전학적 이상을 진단하기 위한 비침습적 진단시스템
KR101739535B1 (ko) 2016-01-25 2017-05-24 지놈케어 주식회사 태아의 염색체이수성을 검출하는 방법
WO2017213470A1 (fr) * 2016-06-10 2017-12-14 이원다이애그노믹스(주) Procédé et appareil de test prénatal non invasif basé sur des scores z multiples
KR102142914B1 (ko) * 2018-09-06 2020-08-11 이원다이애그노믹스(주) 모체 혈액 유래 무세포 dna 단편을 이용한 비침습적 산전 검사 방법
KR102319447B1 (ko) 2019-11-28 2021-10-29 주식회사 쓰리빌리언 Ngs를 이용한 열성유전병 원인 유전변이 판별 방법 및 장치
KR102687080B1 (ko) 2023-10-18 2024-07-22 주식회사 쓰리빌리언 데이터 부재 영역을 이용한 유전자 복제수 이상 탐지 시스템

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109988833A (zh) * 2017-12-29 2019-07-09 南京格致基因生物科技有限公司 宫颈癌的判断方法及系统
WO2020226528A1 (fr) * 2019-05-08 2020-11-12 Общество с ограниченной ответственностью "ГЕНОТЕК ИТ" Procédé pour déterminer le caryotype foetal chez une femme enceinte

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