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Family-based low-depth sequencing method for detecting chromosome monoparental disomes

A deep sequencing and chromosome technology, applied in the field of prenatal diagnosis molecular genetics detection, can solve the problems that the detection system cannot judge, there is no research detection problem, etc.

Pending Publication Date: 2021-11-02
广东博奥医学检验所有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The sequencing depth of CNV-seq in clinical application is generally 0.05X to 0.5X. In this low-coverage whole-genome sequencing data file, most of the read coverage depth of detectable SNP sites is 1X. At this time, the detection The system cannot make accurate judgments on the genotype of each locus, and no research suggests that this depth can better solve the detection problem of AOH or UPD

Method used

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  • Family-based low-depth sequencing method for detecting chromosome monoparental disomes
  • Family-based low-depth sequencing method for detecting chromosome monoparental disomes
  • Family-based low-depth sequencing method for detecting chromosome monoparental disomes

Examples

Experimental program
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Effect test

Embodiment 1

[0104] Example 1: Non-invasively found that the Z value of chromosome 16 was abnormal, and the karyotype of amniocentesis was normal. The microarray showed that there was ROH in the short arm of chromosome 16. After STR, the parent microarray verified that the fetus was matUPD16.

[0105] Noninvasive results such as figure 2 Shown: suggesting a high risk of trisomy 16;

[0106] The results of the gene chip were as image 3 Shown:

[0107] ROH exists on fetal chromosome 16, such as Figure 4 Shown, verified as 16matUPD;

[0108] The family CNV-seq results are as follows:

[0109] Such as Figure 5 As shown, the fetus: No. EO900080FT, 46, XX, no obvious copy number abnormalities

[0110] Such as Figure 6 Shown, mother: No. EO900093BT, 46, XX, no obvious copy number abnormalities

[0111] Such as Figure 7 As shown, father: No. EO900094BT, 46, XY, no obvious copy number abnormalities

[0112] The cdSNP consistency analysis was performed on the original CNV-seq data of...

Embodiment 2

[0123] Example 2: Non-invasive T15, amniocentesis with normal karyotype, microarray showing ROH on chromosome 15, which was verified as patUPD15 by family STR.

[0124] Such as Figure 8 and Figure 9 Shown is the CMA report of the fetus;

[0125] The family CNV-seq results are as follows:

[0126] Such as Figure 10 Shown, fetus: No. EO002181DT, 46, XX, no obvious copy number abnormalities

[0127] Such as Figure 11 Shown, mother: No. E0000165BT, 46, XX, no obvious copy number abnormalities

[0128] Such as Figure 12 As shown, father: No. E0000166BT, 46, XY, no obvious copy number abnormalities

[0129] The cdSNP consistency analysis was performed on the original CNV-seq data of the above families:

[0130] 2.1 Sequence alignment, the three raw data files of family CNV-seq were compared by BWA to obtain three files with alignment information;

[0131] 2.2 Sequence filtering;

[0132] 2.3 Select the SNP site data set with high frequency heterozygosity in the popula...

Embodiment 3

[0140] Example 3: Non-invasive normal, amniocentesis with normal karyotype, the microarray showed that there was ROH on chromosome 6, and the parent microarray verified that the ROH of No. 6 was not UPD, and the ROH might be caused by kinship.

[0141] Such as Figure 13 and Figure 14 Shown is the CMA report of the fetus;

[0142] The heterozygous signal map of fetal chromosome 6, suggesting that there is a 10.6Mb region of homozygosity (ROH) at 6q24.3q25.3.

[0143] Such as Figure 15 As shown, the CMA analysis results of the family on chromosome 6 suggest that the ROH phenomenon is not caused by UPD.

[0144] The family CNV-seq results are as follows:

[0145] Such as Figure 16 Shown, fetus: number EO001478DT, 46, XY, dup(4): 168.3Mb-169.4Mb, consistent with the copy number abnormality reported by CMA.

[0146] Such as Figure 17 As shown, mother: No. EO001620BT, 46, XX, no obvious copy number abnormalities

[0147] Such as Figure 18As shown, the father: number E...

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Abstract

The invention discloses a family-based low-depth sequencing method for detecting chromosome monoparental disomes by utilizing the characteristic that a large number of cdSNPs exist in chromosomes between samples of a fetus and parents, and the method comprises the following steps: S1, sequence comparison: comparing three original data files of family CNV-seq to obtain three files with comparison information; S2, performing sequence filtering; S3, selecting a high-frequency heterozygous SNP site data set of the crowd; S4, obtaining a cdSNP site list; S5, counting the total CR value of the mother-child and father-child samples and the CR value of each chromosome; and S6, performing fetal chromosome UPD analysis according to the CR value to obtain a conclusion. According to the method, the CNV-seq detection process and the detection cost do not need to be changed, analysis and comparison are carried out only by utilizing the CNV-seq original data file of the family, whether UPD exists in the chromosome of the fetus or not can be identified, and the method has the advantages of low detection cost and high detection accuracy.

Description

technical field [0001] The invention relates to the technical field of prenatal diagnosis molecular genetics detection, in particular to a method for detecting chromosomal uniparental disomy based on family low-depth sequencing. Background technique [0002] The classic theory of meiosis in human developmental biology holds that during the formation of fertilized eggs, the sperm and eggs of both sexes go through meiosis, and their respective chromosomes are reduced from 23 pairs to 23 chromosomes, and after fertilization and recombination, Fertilized eggs and subsequent embryonic cells are restored to 23 pairs of chromosomes. Therefore, under normal circumstances, half of the chromosomes of the fetus should come from the father and the other half from the mother. If this process is abnormal, it may lead to the occurrence of certain genetic diseases. [0003] Uniparental disomy (UPD) refers to a pair of homologous chromosomes or partial segments of chromosomes originating f...

Claims

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Application Information

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IPC IPC(8): G16B30/10
CPCG16B30/10
Inventor 陈样宜黄楷胜刘燕霞刘远如焦伟刚
Owner 广东博奥医学检验所有限公司
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