CN103436609A - Method for noninvasive prenatal disgnosis of congenital deafness genetic disease - Google Patents
Method for noninvasive prenatal disgnosis of congenital deafness genetic disease Download PDFInfo
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- CN103436609A CN103436609A CN2013103487240A CN201310348724A CN103436609A CN 103436609 A CN103436609 A CN 103436609A CN 2013103487240 A CN2013103487240 A CN 2013103487240A CN 201310348724 A CN201310348724 A CN 201310348724A CN 103436609 A CN103436609 A CN 103436609A
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Abstract
The invention belongs to the technical field of gene diagnosis, and provides a method for noninvasive prenatal disgnosis of a congenital deafness genetic disease through the technology taking gene chips as a platform. Each microarray gene chip comprises a chip base and probes fixed on the chip base, and the probes have the nucleotide sequences which are as shown in the table 1-2. The diagnosis method comprises the steps as follows: preparation of to-be-tested DNA, multiple PCR amplification, chip hybridization, data processing and image analysis, chip scanning and result obtaining. At the same time, the invention comprises a kit for the noninvasive prenatal disgnosis of the congenital deafness genetic disease, and the kit comprises the microarray gene chips; the method for noninvasive prenatal disgnosis of the congenital deafness genetic disease is simple and convenient; detection has the characteristics of high throughput, good specificity and high sensitivity, the situation that whether each locus belongs to the wild type or the mutant type can be quickly screened, and the diagnosis of the congenital deafness genetic disease can be improved to the gene level; since the noninvasive prenatal disgnosis technology is adopted, the cost is reduced, the time is saved, and the pain of patients is further reduced.
Description
Technical field
The invention belongs to the gene diagnosis technical field, be specifically related to a kind of method without wound antenatal diagnosis congenital deafness inherited disease that the cDNA microarray technology is platform technology of take.
Background technology
Deaf disease is to affect human health and the common cause that causes mankind's deformity, and China has more than 2,000 ten thousand the deaf-mutes now, accounts for Disabled persons's sum 1/3, and with annual newborn infant's 30,000 speed increment.The deaf reason occurred, whether having heredity, fertility or whether again give birth to safety, is the problem that deafness patient and deaf family very are concerned about.According to various countries statistics, while having 1/2000 (0.05%) one 1/1000 (0.1%) children to be born, be utmost point severe deafness; Simultaneously, the Childhood of over half, deafness is because inherited genetic factors causes.In addition in a large amount of Delayed onset auditory dysesthesia patients, also there are many patients to be caused a disease by the genetic flaw of self, or increase and cause a disease causing deaf environmental factors susceptibility because genetic flaw and polymorphism cause.
In hereditary hearing impairment, have 70% for NSHI (nonsyndromie hearingim pairment nonsyndromic deafness), about 75%～85% NSHI shows as the autosomal recessive inheritance pattern, 15%～24% is the autosomal dominant inheritance pattern, and all the other 1%～2% are X linkage inheritance pattern.Completing and the research of deaf disease mechanism of causing a disease deepened continuously along with the Human Genome Project, the Study of Etiology of hereditary hearing impairment has had remarkable progress, have at least at present more than 60 deaf genes to be cloned, these find that our hereditary hearing impairment of prompting has very high genetic heterogeneity, the gene diagnosis of hereditary hearing impairment relates to the detection of a plurality of genes, thereby has increased the weight of the difficulty of hereditary hearing impairment molecular diagnosis.
A large amount of researchs show, the pathologic sudden change of GJB2, SLC26A4 (PDS) and chondriogen (mtDNA) has caused most hereditary hearing impairment, and are proved to be that three kinds of Chinese deaf and dumb crowds are modal causes deaf transgenation.Utilize the gene diagnosis technology to these three common gene tests, can cause deaf transgenation at about 70% hereditary hearing impairment Finding case, this not only can the clear and definite cause of disease of deafness patient, also makes deaf genetic counseling and antenatal diagnosis become possibility.This not only makes the clear and definite cause of disease of deafness patient, also for deaf genetic counseling provides theoretical foundation and scientific method, makes congenital deafness antenatal diagnosis result more objective and accurate.
At present, the technology that can be used for the congenital deafness antenatal diagnosis mainly contains the technology such as polymerase chain reaction, fluorescence in situ hybridization and gene chip.Polymerase chain reaction (polymerase chain reaction, PCR) this technology is one of important diagnostic techniques in molecule laboratory, amplification of DNA fragments, for genetic analysis, comprises nest-type PRC, multiplex PCR, fluorescent PCR, quantitative fluorescent PCR etc. in vitro.Be mainly used in diagnosis and the polymorphism analysis of the disease that causes due to genetically deficient, near Disease-causing gene, find several DNA polymorphisms closely linked with it site, by linkage analysis, diagnose the detection with the carrier.May cause mistaken diagnosis but round pcr is subject to the possible impact of amplification efficiency, allele dropout, pollution, and PCR only can detect known abnormal.Fluorescence in situ hybridization (fluorescence in situ hybridization, FISH) this technology is to utilize fluorescein-labeled probe and DNA fragmentation specific hybrid, probe is combined the hybrid molecule formed and can under the fluorescent microscope fluorescence excitation, be shown fluorescent signal with specific DNA fragment, reach the purpose of diagnosis chromosomal disorder according to the type that has that it's too late of decision signal.This method, without cell cultures, only can obtain result in 24 hours, and pollution probability is little, signal is directly perceived, detection time is short, applies more extensive.The probe of fluorescence in situ hybridization comprises following several: centromeric probe (combining centromere probe, CEP), locus specificity probe (focus-specific probe, LSI), telomere probe (telomere probe, Tel), whole chromosome painting probe (whole chromosome probe, WCP) and across breaking point probe (span break-point probe).Apply dissimilar probe and can examination congenital deafness disease gene carrier carry out genetic diagnosis.
PCR and FISH technology become method acknowledged and that in succession use.But these two kinds of methods are the defect of existence itself all, PCR only can detect known abnormal.Fluorescence in situ hybridization technique is to utilize the hybridization of fluorescein-labeled probe and chromosome specific, and according to microscopic examination fluorescent signal result of determination normally whether, signal is directly perceived, detection time is short.But, because the sample source of check is very limited, 1-2 blastomere cell only arranged usually.The FISH technology only can detect a small amount of karyomit(e) and gene.Yet the congenital deafness disease relate to many chromosomal a plurality of genes, the FISH technology can not meet the needs of antenatal congenital deafness examination.
Biochip technology refers to and is fixed on upholder the specific oligonucleotides fragment as probe, the target DNA fragment that mixes marker by the amplification of the technology such as PCR after, then by the base pairing principle, hybridized, by signal detection system, chip is scanned again, and adapted correlation analysis software is made comparisons and detects the signal on each probe.This technology is widely used in the disease detection field at present.By detecting the common hereditary hearing impairment Disease-causing gene sudden change of pregnant woman and spouse thereof Carriage, but early discovery hereditary hearing impairment Fertility reproductive risk effectively reduces the sickness rate of hereditary hearing impairment in conjunction with antenatal diagnosis.The methods such as relative pcr amplification order-checking, the hereditary hearing impairment genechip detection has the advantages such as the credible result degree is high, flux is large, speed is fast, workable, is applicable to the antenatal gene test of hereditary hearing impairment.
Traditional congenital deafness diagnostic method need to carry out amniocentesis to the pregnant woman in pregnant 17-20 week, amniocyte and amniotic fluid culturing cell are carried out to corresponding deaf gene complete sequence amplification order-checking, detected thereby Mr. and Mrs both sides are carried to the congenital deafness Disease-causing gene, and carried out the assessment of hereditary hearing impairment Fertility reproductive risk.This has strengthened the time of detecting greatly, and has brought the dual misery on the mind & body to examined person, is not suitable for antenatal diagnosis.Therefore, finding a kind of highly sensitive method without wound antenatal diagnosis congenital deafness inherited disease is very important.
Summary of the invention
Content of the present invention is to overcome the deficiencies in the prior art, and a kind of method without wound antenatal diagnosis congenital deafness inherited disease that biochip technology is platform technology of take is provided.The diagnostic techniques simple operating steps of Diagnosis of Congenital deaf inheritance disease of the present invention, have high-throughout characteristics, variation that can rapid screening congenital deafness genes involved, and the diagnosis of congenital deafness disease is brought up on gene level; The specificity detected is good, and has high resolving power, highly sensitive, characteristics accurately and rapidly, adopts without wound antenatal diagnosis technology, the cost-saving time, reduces patient's misery.Can, for the diagnosis of antenatal congenital hereditary disease, without wound antenatal diagnosis field, there are very large potentiality.
Technical scheme of the present invention realizes by the following technical solutions.
First aspect, the present invention relates to the cDNA microarray of a kind of distribution as the nucleotide sequence of table as shown in 1-1, comprises the sheet base of micro-array chip and be fixed on the probe of the congenital deaf-related gene of detection on the sheet base.
Preferably, the sequence of described probe is as shown in table 1-1:
Table 1-1. probe sequence
| Sequence number | The probe title | Sequence (5 '-3 ') |
| P1 | mtDNA-W1 | AGTACAGCGTCAAAGATGTAATGAG |
| P2 | mtDNA-M1 | TAAAACTTTCTTTATGCACCCTACTA |
| P3 | mtDNA-W2 | AGTACCATGATGATACCGGAA |
| P4 | mtDNA-M2 | GAATGCACAATCATGATGATACCGG |
| P5 | SLC26A4-1-W1 | CAGACTTTGCTCGAACATTAAACAG |
| P6 | SLC26A4-1-M1 | TCCACATTTATTGTTTAATTAATTA |
| P7 | SLC26A4-1-W2 | ATGCTTTCGATTTAAATGGTGAT |
| P8 | SLC26A4-1-M2 | TCTGTGATCGAAAAGTAATGAGC |
| P9 | SLC26A4-2-W1 | TCAACAGCTCTAACTTGCAACC |
| P10 | SLC26A4-2-M1 | AAATAAATTGTTTAATTGGTTACA |
| P11 | SLC26A4-3-W1 | AACATCGCATTGTCGTGTTGCCTGT |
| P12 | SLC26A4-3-M1 | GAGTACCTGAGTAATGTCTGGTGCA |
| P13 | GJB2-W1 | TGCACCAATCACTCAGGTACTCCGA |
| P14 | GJB2-M1 | CTGACACGGGCACTCTTCGC |
| P15 | GJB2-W2 | CGTCGAATACTTCGAARAGAAGA |
| P16 | GJB2-M2 | TTGCTGCAGCTAGTCTTAGCTTCG |
。
Preferably, described base is slide glass, silicon chip or film.
Preferably, the material of described base is macromolecular material.
Second aspect, the present invention relates to the preparation method of aforesaid cDNA microarray, comprise the steps: the acid-base pretreatment of sheet base, the aldehyde radical processing, the isothiocyanic acid processing, the design of chip probe, the some system of probe, toast 10min by slide at 80 ℃ immediately, make the microarray slide, be stored in the box with siccative, room temperature preservation, obtain.
The third aspect, the present invention relates to the operation steps of aforesaid cDNA microarray, comprises the steps: DNA preparation to be measured, the multiplex PCR amplification, and Product Labeling, chip hybridization, data processing and image analysis, chip scanning, obtain result.
Preferably, increase needed amplimer as shown in table 1-2:
The table 1-2. needed amplimer that increases
Fourth aspect, the present invention relates to the test kit of a kind of cDNA microarray without wound antenatal diagnosis congenital deafness inherited disease, and described test kit comprises aforesaid cDNA microarray.
The nothing wound antenatal diagnosis congenital deafness inherited disease micro-array chip of cf-fDNA based on maternal blood of the present invention, to take the cf-fDNA (fetus and parent dissociative DNA mixture) of maternal blood to be measured to carry out the multiplex PCR amplification as template, by after the pcr amplification product obtained, hybridized with chip, according to results of hybridization, determined whether fetus carries congenital deaf-related gene.
The present invention has following beneficial effect: the diagnostic method of nothing wound antenatal diagnosis congenital deafness inherited disease of the present invention is easy, only needs, by after DNA to be measured is passed through to pcr amplification, with chip hybridization scanning analysis, can obtain result; Detection has high-throughout characteristics, variation that can rapid screening congenital deafness genes involved, and the congenital deafness medical diagnosis on disease is brought up on gene level; The specificity detected is good, and has high resolving power, highly sensitive, characteristics accurately and rapidly, adopts without wound antenatal diagnosis technology, the cost-saving time, reduces patient's misery.
The accompanying drawing explanation
Fig. 1 is that fetus mixes the scintigram that carries deaf mutator gene mtDNA-1, SLC26A4 and GJB2.
Fig. 2 is the scintigram that fetus does not carry any congenital deafness genes involved.
Fig. 3 chip probe sequential schematic
embodiment
Below in conjunction with specific embodiment, further explain the present invention.Be interpreted as, these embodiment are only for the present invention is described, and are not used in restriction specific embodiment of the invention scope.It in lower routine embodiment, is the experimental technique that indicates actual conditions, usually according to normal condition, Sambrook equimolecular clone for example: laboratory manual is shown in the condition described in NEW YORK COLD Spring harbor laboratory press version in 1989, or the condition of advising according to manufacturer.
Micro-array chip of the present invention adopts a kind of method without wound antenatal diagnosis congenital deafness inherited disease that biochip technology is platform technology of take, and the phenomenon of common congenital deafness in the diagnosis crowd, classify probe as with the nucleotides sequence as shown in table 1-2.Totally 20 probes on each chip, the wild-type of eight relevant mutational sites of three genes involveds of the described congenital deafness of described microarray and 16 probes of saltant type, probe sequence and title are in Table 1-1.2 of positive quality control probes, 1 of negative Quality Control probe, 1 of blank probe.Described probe title as table with special instrument be point sample instrument by 20 probe point samples to the slide that covers particular medium, according in order successively, every probe triplicate, target spot is sequentially as shown in Figure 3.Sample is prepared, multiplex PCR amplification, after chip hybridization, according to the fluorescent signal value size in corresponding site, judge whether this sample to be tested carries the congenital deafness genes involved.
The present invention relates to the preparation method of aforesaid cDNA microarray, comprise the steps: the acid-base pretreatment of sheet base, the aldehyde radical processing, isothiocyanic acid processing, the design of chip probe, the point system of probe, immediately slide is toasted to 10min at 80 ℃, make the microarray slide, be stored in the box with siccative, room temperature preservation, obtain.
Concrete operation step of the present invention
1. DNA preparation to be measured and amplification
Prepare plasma sample, and adopt blood DNA to extract test kit extraction DNA, and utilize foregoing primer to be increased.
2. hybridization
After sex change 10min, be placed in immediately ice bath 5min after PCR product and hybridization solution equal proportion are mixed under 95 ℃ of conditions, simultaneously by chip in 0.2%SDS after rinsing 20s, then in ultrapure water rinsing 5s.Get rid of the water on coring sheet surface, dry at ambient temperature.
Get the amplified production 10 μ l of sex change, carefully add in the chip reaction zone, make its be evenly distributed (with hybrid mixed liquid, cover the hybridization district and do not overflow and be as the criterion).When hybrid mixed liquid is added to the chip reaction zone, should note making the rifle head to contact with chip, in order to avoid affect probe array.Chip is flat in hybridizing box, and in the water-bath of hybridization temperature undetermined, hybridization is 1 hour.Should prevent during hybridization that condensing drip from dropping on chip; Care should be used to during mobile hybridizing box, in case the reaction solution crossed contamination of each reaction zone.After hybridization finishes, by chip rinsing in the SSC washings.Take out chip, get rid of the liquid remained on chip, room temperature is dried.
3. data processing and image analysis
Results of hybridization adopts the laser co-focusing gene chip scanning instrument to be scanned, and adopts signal analysis software to be analyzed.
4. chip compliance test result
Using said chip to detect through sequence verification is 20 parts, normal people's sample and 6 parts, mtDNA saltant type sample, 10 parts, SLC26A4-1 saltant type sample, 8 parts, SLC26A4-2 saltant type sample, 5 parts, SLC26A4-3 saltant type sample, 7 parts, GJB2 saltant type sample, amount to 56 parts (comprise and mix case), detected result is all consistent with the direct Sequencing result, possesses specificity while having proved chip detection deaf gene sudden change of the present invention.
Claims (8)
1. the cDNA microarray without wound antenatal diagnosis congenital deafness inherited disease, comprise the sheet base and be fixed on the probe of the detection congenital deafness genes involved on the sheet base.
2. nothing claimed in claim 1 is created the cDNA microarray of antenatal diagnosis congenital deafness inherited disease, and on it, the sequence of probe is as follows:
。
3. nothing according to claim 1 is created the cDNA microarray of antenatal diagnosis congenital deafness inherited disease, and it is characterized in that: described base is slide glass, silicon chip or film.
4. nothing according to claim 1 is created the cDNA microarray of antenatal diagnosis congenital deafness inherited disease, and it is characterized in that: the material of described base is macromolecular material.
5. the preparation method of the cDNA microarray without wound antenatal diagnosis congenital deafness inherited disease according to claim 1, comprise the steps: the acid-base pretreatment of sheet base, the aldehyde radical processing, the isothiocyanic acid processing, the design of chip probe, the some system of probe, immediately slide is toasted to 10min at 80 ℃, make the microarray slide, be stored in the box with siccative, room temperature preservation and get final product.
6. the using method of the cDNA microarray without wound antenatal diagnosis congenital deafness inherited disease according to claim 1, it is characterized in that comprising the steps: DNA preparation to be measured, multiplex PCR amplification, chip hybridization, data processing and image analysis, chip scanning obtains result.
7. nothing according to claim 5 is created the using method of the cDNA microarray of antenatal diagnosis congenital deafness inherited disease, it is characterized in that primer pair used in described pcr amplification is as shown in the table:
8. the test kit for nothing wound antenatal diagnosis congenital deafness inherited disease, is characterized in that described test kit comprises cDNA microarray claimed in claim 1.
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Cited By (6)
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| EP2937422A1 (en) * | 2014-04-23 | 2015-10-28 | Berry Genomics Co., Ltd. | A method and a kit for non-invasively detecting fetal deafness pathogenic gene mutations |
| CN105624796A (en) * | 2014-11-07 | 2016-06-01 | 天津华大基因科技有限公司 | Chip and uses of chip in deafness related gene detection |
| CN109355374A (en) * | 2018-11-30 | 2019-02-19 | 中国人民解放军第四军医大学 | Large Vestibular Aqueduct/Pendred syndrome Disease-causing gene SLC26A4 mutation detection kit |
| CN109680057A (en) * | 2018-12-29 | 2019-04-26 | 中国人民解放军第四军医大学 | Large Vestibular Aqueduct/Pendred syndrome Disease-causing gene SLC26A4 abrupt climatic change kit |
| CN110628876A (en) * | 2019-09-28 | 2019-12-31 | 北京安博迪恩生物科技有限公司 | Detection method of hereditary hearing loss gene |
| WO2020052603A1 (en) * | 2018-09-14 | 2020-03-19 | 张娇 | Gene chip and kit for noninvasive prenatal testing of bilateral cupped ear deformity, and application method of gene chip |
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Cited By (8)
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| CN109680057A (en) * | 2018-12-29 | 2019-04-26 | 中国人民解放军第四军医大学 | Large Vestibular Aqueduct/Pendred syndrome Disease-causing gene SLC26A4 abrupt climatic change kit |
| CN110628876A (en) * | 2019-09-28 | 2019-12-31 | 北京安博迪恩生物科技有限公司 | Detection method of hereditary hearing loss gene |
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Application publication date: 20131211 |