WO2022078099A1 - Mrkh综合征诊断标记物及其在制备mrkh综合征诊断试剂盒中的应用 - Google Patents
Mrkh综合征诊断标记物及其在制备mrkh综合征诊断试剂盒中的应用 Download PDFInfo
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- WO2022078099A1 WO2022078099A1 PCT/CN2021/116122 CN2021116122W WO2022078099A1 WO 2022078099 A1 WO2022078099 A1 WO 2022078099A1 CN 2021116122 W CN2021116122 W CN 2021116122W WO 2022078099 A1 WO2022078099 A1 WO 2022078099A1
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- 208000034025 Mayer-Rokitansky-Küster-Hauser syndrome Diseases 0.000 title claims abstract description 86
- 239000003550 marker Substances 0.000 title claims abstract description 17
- 238000009007 Diagnostic Kit Methods 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 101150059272 TBX6 gene Proteins 0.000 claims abstract description 37
- 230000035772 mutation Effects 0.000 claims abstract description 37
- 239000012634 fragment Substances 0.000 claims abstract description 8
- 230000035935 pregnancy Effects 0.000 claims description 14
- 230000003321 amplification Effects 0.000 claims description 13
- 238000003199 nucleic acid amplification method Methods 0.000 claims description 13
- 238000009609 prenatal screening Methods 0.000 claims description 11
- 208000026350 Inborn Genetic disease Diseases 0.000 claims description 9
- 208000016361 genetic disease Diseases 0.000 claims description 9
- 238000012216 screening Methods 0.000 claims description 9
- 230000001605 fetal effect Effects 0.000 claims description 8
- 238000011144 upstream manufacturing Methods 0.000 claims description 5
- 102220024547 rs59161567 Human genes 0.000 claims 1
- 210000005259 peripheral blood Anatomy 0.000 abstract description 7
- 239000011886 peripheral blood Substances 0.000 abstract description 7
- 238000007480 sanger sequencing Methods 0.000 abstract description 7
- 108020004414 DNA Proteins 0.000 abstract description 6
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- 230000014509 gene expression Effects 0.000 abstract description 4
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- 102220101562 rs1800499 Human genes 0.000 description 29
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- 208000031404 Chromosome Aberrations Diseases 0.000 description 4
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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
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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
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention belongs to the technical field of medical detection, and particularly relates to a MRKH syndrome diagnostic marker and its application in the preparation of a MRKH syndrome diagnostic kit.
- the abnormal development of the Müllerian duct during the embryonic period of females leads to congenital absence of vagina with no uterus or only primordial uterus, namely MRKH syndrome (Mayer-Rokitansky-Küster-Hauser syndrome), with an incidence rate of 1/5000-1/4000.
- the main clinical features include: no uterus or solid primordial uterine nodules, a small number of patients have functional endometrium but uterine dysplasia; complete absence of vagina, or absence of upper 2/3 and lower 1/3 of acupoints The top is a blind end; the fallopian tubes and ovaries are normally developed, the secondary sexual characteristics are normal female, and the chromosomal karyotype is female karyotype 46, XX.
- MRKH syndrome is mainly divided into two types, among which type I (simple type) is characterized by simple abnormal development of the uterus and vagina, while the development of the urinary system and skeletal system is normal, which is the most common type; type II (complex type) is characterized by the removal of the uterus , In addition to vaginal dysplasia, it is also accompanied by urinary, skeletal or other system development abnormalities.
- chromosomal aberrations may be the pathogenic factors of MRKH syndrome.
- the researchers screened related genes by detecting chromosomal aberration sites and identified the pathogenicity of related genes in MRKH syndrome.
- Previous literature reported that segmental deletion of chromosome 16p11.2 region was found in about 2% of patients with MRKH syndrome, which was one of the most common chromosomal aberrations in MRKH syndrome, and the TBX6 gene located in this region was considered to be more likely. Large suspected causative genes. Sandakan et al.
- splice site mutation (622-2A>T) of the TBX6 gene in patients with MRKH syndrome, which is located at the splice acceptor site of exon 5, so this mutation is likely to reduce the splicing of exon 5.
- Correct splicing; Tewes et al. found 5 missense mutations in the TBX6 gene among 167 MRKH patients; Tbx6 knockout female mice also showed genitourinary malformations. Therefore, researchers speculate that TBX6 gene mutation may be one of the causes of MRKH syndrome, and early detection of gene mutation sites can achieve early and early diagnosis.
- the purpose of the present invention is to provide a diagnostic marker for MRKH syndrome and its application in the preparation of a diagnostic kit for MRKH syndrome.
- a MRKH syndrome diagnostic marker is a TBX6 gene fragment with a mutation site c.423G>A.
- the present invention provides the application of the above-mentioned MRKH syndrome diagnostic markers in the preparation of MRKH syndrome diagnostic kits.
- MRKH can be assisted. Rapid diagnosis of the syndrome.
- the present invention does not require the length of the TBX6 gene fragment for which the primers are designed (ie, the length of the MRKH syndrome diagnostic marker), as long as the TBX6 gene fragment carries the mutation site c.423G>A.
- a TBX6 gene fragment with 200 bp bases before and after the mutation site c.423G>A can be selected as a template to design specific amplification primers.
- the present invention also provides a MRKH syndrome diagnostic kit, which at least comprises specific amplification primers for amplifying the above MRKH syndrome diagnostic markers.
- the specific amplification primers are:
- Upstream primer 5'-AACCCTATCCTGGAGTCCCA-3';
- Downstream primer 5'-TTTCTCTGACAGCTCTGGGG-3'.
- the present invention also provides the application of the above-mentioned MRKH syndrome diagnostic marker in preparing a fetal MRKH syndrome prenatal screening kit.
- prenatal screening of MRKH syndrome during pregnancy it is possible to know whether the fetus has MRKH syndrome as early as possible, and reduce the incidence of the disease from the source.
- the present invention also provides a fetal MRKH syndrome prenatal screening kit, which at least comprises the specificity for amplifying the above-mentioned MRKH syndrome diagnostic markers Amplification primers.
- the present invention also provides the application of the above-mentioned MRKH syndrome diagnostic marker in the preparation of a male pre-pregnancy genetic disease screening kit.
- the present invention also provides a male pre-pregnancy genetic disease screening kit, which at least comprises specific amplification primers for amplifying the above-mentioned MRKH syndrome diagnostic markers.
- the present invention provides the application of the above-mentioned MRKH syndrome diagnostic markers in the preparation of MRKH syndrome diagnostic kits, by collecting peripheral blood of a subject, obtaining genomic DNA, and detecting whether the mutation exists in the TBX6 gene by Sanger sequencing
- the present invention also provides a fetal MRKH syndrome prenatal screening kit, which can be used to perform prenatal screening of MRKH syndrome during pregnancy, so as to understand the fetus as soon as possible. Whether there is the possibility of suffering from MRKH syndrome, reduce the birth rate of babies with birth defects, and reduce the incidence of the disease from the source.
- the test kit can be used to screen whether the male TBX6 gene carries the mutation site c.423G>A before pregnancy or marriage, and it can also prevent the birth of children with MRKH syndrome as soon as possible.
- Fig. 1 is a graph showing the results of Sanger sequencing on peripheral blood DNA of patients with MRKH;
- the point of the arrow is the mutation site c.423G>A;
- Fig. 2 is a graph showing the results of agarose gel electrophoresis analysis of RNA extraction from peripheral blood of tested MRKH patients and their parents and reverse transcription into cDNA for PCR amplification;
- Figure 3 is a graph showing the results of sequencing analysis of the gel electrophoresis products of the tested MRKH patient and the father carrying the TBX6 gene mutation (c.423G>A);
- WT indicates the normal TBX6 gene without mutation
- c.423G>A indicates the TBX6 gene with the mutation site c.423G>A
- Exon indicates the exon.
- the patentee recruited a total of 442 MRKH patients from Peking Union Medical College Hospital (PUMCH) and Shenzhen Luohu Hospital, who were diagnosed with MRKH by gynecological ultrasound, pelvic MRI, karyotype analysis and collected medical records. Each subject signed an informed consent form, and the ethics committees of Peking Union Medical College Hospital and Shenzhen Luohu Hospital approved the study.
- Peripheral blood DNA was extracted from each subject separately, and exome sequencing was performed on all subjects.
- Illumina paired-end libraries were prepared from DNA samples and exome-captured, then sequenced on the Illumina HiSeq 4000 platform; variants were called and filtered using an in-house developed analysis strategy (Peking Union Medical College Pipeline, PUMP).
- the patentee first confirmed that the mutation site was a true mutation through Sanger sequencing.
- the sequencing results are shown in Figure 1, and the point indicated by the arrow is the mutation site; the primers used for Sanger sequencing are shown in Table 1.
- upstream primer 5 -AACCCTATCCTGGAGTCCCA-3’ downstream primer 5'-TTTCTCTGACAGCTCTGGGG-3'
- the verification method includes: collecting the peripheral blood of patients and their parents, extracting RNA using a conventional kit, and reverse transcribing it into cDNA, and using pre-designed primers to amplify the cDNA by nested PCR. Nested PCR amplification primers are shown in Table 2.
- the amplified product of the second round of PCR reaction was used for agarose gel electrophoresis to analyze PCR product fragments, and at the same time for sequencing analysis.
- the patentee has launched a MRKH syndrome diagnostic kit, a fetal MRKH syndrome prenatal screening kit and a male pre-pregnancy genetic disease screening kit, all of which are in the kits.
- a MRKH syndrome diagnostic kit a fetal MRKH syndrome prenatal screening kit and a male pre-pregnancy genetic disease screening kit, all of which are in the kits.
- the MRKH syndrome diagnostic kit can be used for MRKH screening in female patients with suspected MRKH syndrome, as an auxiliary means for the diagnosis of MRKH syndrome.
- the fetal MRKH syndrome prenatal screening kit is used for prenatal screening of MRKH syndrome during pregnancy, which can identify whether the fetus has MRKH syndrome as soon as possible, and reduce the incidence of MRKH syndrome from the source.
- the male pre-pregnancy genetic disease screening kit is used to screen men for genetic diseases before pregnancy, and can also prevent the birth of children with MRKH syndrome as early as possible.
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Abstract
Description
上游引物 | 5’-AACCCTATCCTGGAGTCCCA-3’ |
下游引物 | 5’-TTTCTCTGACAGCTCTGGGG-3’ |
Claims (10)
- MRKH综合征诊断标记物,其特征在于,为带有突变位点c.423G>A的TBX6基因片段。
- 如权利要求1所述的MRKH综合征诊断标记物在制备MRKH综合征诊断试剂盒中的应用。
- 一种MRKH综合征诊断试剂盒,其特征在于,至少包含用于扩增如权利要求1所述的MRKH综合征诊断标记物的特异性扩增引物。
- 如权利要求3所述的MRKH综合征诊断试剂盒,其特征在于,所述的特异性扩增引物为:上游引物:5’-AACCCTATCCTGGAGTCCCA-3’;下游引物:5’-TTTCTCTGACAGCTCTGGGG-3’。
- 如权利要求1所述的MRKH综合征诊断标记物在制备胎儿MRKH综合征产前筛查试剂盒中的应用。
- 一种胎儿MRKH综合征产前筛查试剂盒,其特征在于,至少包含用于扩增如权利要求1所述的MRKH综合征诊断标记物的特异性扩增引物。
- 如权利要求6所述的胎儿MRKH综合征产前筛查试剂盒,其特征在于,所述的特异性扩增引物为:上游引物:5’-AACCCTATCCTGGAGTCCCA-3’;下游引物:5’-TTTCTCTGACAGCTCTGGGG-3’。
- 如权利要求1所述的MRKH综合征诊断标记物在制备男性孕前遗传病筛查试剂盒中的应用。
- 一种男性孕前遗传病筛查试剂盒,其特征在于,至少包含用于扩增如权利要求1所述的MRKH综合征诊断标记物的特异性扩增引物。
- 如权利要求9所述的男性孕前遗传病筛查试剂盒,其特征在于,所述 的特异性扩增引物为:上游引物:5’-AACCCTATCCTGGAGTCCCA-3’;下游引物:5’-TTTCTCTGACAGCTCTGGGG-3’。
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CN115976187A (zh) * | 2022-10-11 | 2023-04-18 | 深圳市第二人民医院(深圳市转化医学研究院) | 一种Loeys-Dietz综合征检测试剂盒 |
CN117672502A (zh) * | 2024-01-31 | 2024-03-08 | 中国医学科学院北京协和医院 | 一种mrkh综合征的预测方法、系统和设备 |
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CN112626190A (zh) * | 2020-10-15 | 2021-04-09 | 中国医学科学院北京协和医院 | Mrkh综合征诊断标记物及其在制备mrkh综合征诊断试剂盒中的应用 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115976187A (zh) * | 2022-10-11 | 2023-04-18 | 深圳市第二人民医院(深圳市转化医学研究院) | 一种Loeys-Dietz综合征检测试剂盒 |
CN117672502A (zh) * | 2024-01-31 | 2024-03-08 | 中国医学科学院北京协和医院 | 一种mrkh综合征的预测方法、系统和设备 |
CN117672502B (zh) * | 2024-01-31 | 2024-05-03 | 中国医学科学院北京协和医院 | 一种mrkh综合征的预测方法、系统和设备 |
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