Fetal Mutation Detection via Targeted cfDNA Sequencing
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Solution Overview
Problem
Current methods for non-invasive prenatal diagnosis of fetal gene mutations, particularly for single-gene defects, face challenges in detecting point mutations due to the high maternal DNA background in cell-free fetal DNA, requiring whole-genome sequencing and paternal genetic information, which increases costs and limitations.
Innovation Solution
A computer-implemented method using high-throughput sequencing of cell-free DNA in maternal peripheral blood, aligning data with a reference genome, and performing mixed genotyping with a Bayesian model to identify fetal genotypes without separate sequencing of paternal and maternal samples, reducing costs and improving detection efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If whole-genome sequencing is performed to detect fetal point mutations, then detection precision is improved, but cost increases significantly
Solution Approach 1:
The patent extracts and focuses sequencing efforts only on specific target regions containing known pathogenic genes and mutation sites, rather than sequencing the entire genome. This targeted approach maintains detection precision for clinically relevant mutations while dramatically reducing sequencing costs and data processing requirements.
Solution Approach 2:
The patent applies different sequencing strategies to different genomic regions: high-coverage targeted sequencing for known pathogenic genes, and lower-coverage whole-genome sequencing for de novo mutation detection. This localized quality adjustment optimizes resource allocation by applying high precision only where clinically necessary.
2Reliability
If paternal genetic information is required for fetal mutation detection, then detection reliability is improved, but device complexity and sample requirements increase
Solution Approach 1:
The patent enables the maternal sample to serve multiple functions: it provides both the fetal cell-free DNA for mutation detection and the genetic information needed to identify paternal-derived mutations. By analyzing allele frequencies and comparing with population databases, the system can infer paternal genotype information without requiring separate paternal sampling.
Solution Approach 2:
The maternal plasma sample performs multiple functions: it serves as the source of fetal cell-free DNA for mutation detection, provides genetic background for distinguishing paternal mutations, and enables determination of fetal genotype without requiring separate paternal or fetal samples. This multi-functionality simplifies the overall testing protocol.
3Measurement precision
If high sequencing depth is used to detect fetal mutations, then measurement precision is improved, but loss of energy and time increase
Solution Approach 1:
The patent segments the genome into priority tiers: high-priority target regions (known pathogenic genes) receive high sequencing depth, while other regions receive lower depth. This segmentation allows efficient allocation of sequencing resources, achieving high precision for clinically critical mutations without the time and energy cost of uniformly high-coverage whole-genome sequencing.
Data Source
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AI summary
Provided are a method and a device for detecting a genetic mutation, and a kit for typing genotypes of a pregnant woman and a fetus. The method comprises: performing high-throughput sequencing on free DNA in a pregnant woman's peripheral blood to obtain sequencing data; comparing the sequencing data with reference genome to obtain SNP sites; performing mixed genotyping on each SNP site to obtain target genotypes for each SNP site; and selecting a mutation site that causes the gene mutation from the genotype of the fetus in the target genotypes.