Whole Exome Sequencing for Pathogenic UPD Detection
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Solution Overview
Problem
Current methods for diagnosing uniparental disomy, such as methylation level detection and SNP chip-based methods, are inefficient for genome-wide screening and fail to detect pathogenic micro-mutations, making them unsuitable for comprehensive genetic analysis.
Innovation Solution
A method utilizing whole exome sequencing data to screen for pathogenic mutations and identify uniparental disomy by performing loss of heterozygosity (LOH) and UPD judgments, which includes screening for high-quality mutation sites, removing Y chromosome mutations, and determining the coverage range and frequency of contiguous homozygous sites to assess the risk of pathogenic UPD without additional experiments or labor costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If methylation level detection method is used to diagnose UPD, then small regions on chromosomes can be detected, but the method requires different experiments for different regions resulting in low efficiency and slow speed
Solution Approach 1:
The patent merges multiple detection functions into a single whole exome sequencing experiment. Instead of performing separate methylation detection experiments for different chromosomal regions, the method uses one comprehensive sequencing approach to simultaneously detect pathogenic mutations, small insertions/deletions, copy number variants, and UPD events across the entire genome, thereby resolving the contradiction between detection precision and screening efficiency
Solution Approach 2:
The whole exome sequencing method is designed to perform multiple diagnostic functions simultaneously. It can detect various types of genetic variations (point mutations, indels, CNVs) and UPD events using a single experimental platform, making the method universally applicable for comprehensive genetic analysis without requiring region-specific experiment design
2Area of stationary object
If SNP chip-based method is used to detect UPD, then large contiguous homozygous regions can be detected, but the method has high cost and cannot detect pathogenic micro-mutations
Solution Approach 1:
The patent combines the detection capabilities of SNP chips and sequencing methods into a single whole exome sequencing approach. This merged method maintains the ability to detect large contiguous homozygous regions characteristic of SNP chip methods while simultaneously adding the capability to detect pathogenic micro-mutations, point mutations, and small insertions/deletions that SNP chips cannot detect
Solution Approach 2:
The method changes the detection parameters by using sequencing depth and homozygosity analysis instead of fixed SNP probes. By analyzing the depth of coverage and homozygous variant calls across the exome, the method can dynamically detect both large homozygous regions and small micro-mutations, overcoming the fixed parameter limitations of SNP chip technology
3Adaptability or versatility
If whole exome sequencing is used to detect pathogenic mutations, then comprehensive genetic defects can be detected, but additional experiments are required for UPD detection increasing costs
Solution Approach 1:
The patent makes the whole exome sequencing method universally functional for both mutation detection and UPD detection. By implementing bioinformatics algorithms that analyze homozygosity patterns, coverage depth, and variant calls from the existing sequencing data, the method achieves multi-functionality without requiring additional experiments, thereby eliminating additional costs while maintaining comprehensive detection capability
Solution Approach 2:
The method enables the whole exome sequencing data to serve itself for dual purposes. The same sequencing data that is used to detect pathogenic mutations also contains sufficient information for UPD detection through homozygosity analysis. The bioinformatics pipeline processes the data to simultaneously identify both mutation types, making the system self-sufficient and eliminating the need for separate UPD detection experiments
Data Source
AI summary
A method of screening a pathogenic uniparental disomy and a use thereof is provided. The method includes the steps as follows: obtaining data: obtaining whole exome sequencing data; screening for sites: screening and obtaining mutations under pre-determined conditions; judging LOH: performing LOH judgement according to the mutations obtained above; and judging UPD: judging UPD according to the LOH judgement, wherein when an amount of chromosomes with LOH exceeds 2, a sample is judged as a consanguineous marriage; when there is a single copy of a region with LOH, a sample is judged as a fragment deletion; and other samples are judged as UPD when there are regions with LOH. In the method, specific mutated sites are screened out to perform LOH judgment, to finally obtain the results for UPD judgment. The method is based on the whole exome sequencing data, indicating the risk of pathogenic UPD alongside conventional screening of pathogenic mutations, without additional experiments and labor cost.