Targeted Sequencing for Non-Invasive Fetal Ploidy Detection
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Solution Overview
Problem
Current prenatal diagnosis methods for detecting chromosomal abnormalities in fetuses are either inaccurate or invasive, posing risks such as miscarriage, and there is a need for a non-invasive and accurate method to determine fetal ploidy status.
Innovation Solution
A method involving obtaining DNA samples from mother and fetus, preferentially enriching at polymorphic loci, and using a joint distribution model to calculate allele counts and probabilities for determining fetal ploidy states, which can be performed non-invasively through maternal blood samples.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If invasive procedures like amniocentesis or chorion villus biopsy are used for prenatal diagnosis, then measurement precision of fetal chromosomal status is improved, but object-affected harmful factors increase due to miscarriage risk
Solution Approach 1:
The patent extracts fetal DNA from maternal plasma, separating the diagnostic target (fetal DNA) from the invasive procedure. By analyzing cell-free fetal DNA circulating in maternal blood rather than directly sampling fetal tissue, the method achieves accurate chromosomal status detection without physical intrusion into the fetus, thereby eliminating miscarriage risk while maintaining diagnostic precision
Solution Approach 2:
The patent uses maternal plasma as an intermediary medium to access fetal genetic material. Instead of directly sampling the fetus through invasive procedures, the method analyzes fetal DNA that naturally circulates in maternal circulation, using the maternal plasma as a safe intermediary that provides diagnostic information without exposing the fetus to procedural risks
2Object-affected harmful factors
If non-invasive methods like maternal serum hormone level testing or ultrasound measurements are used, then object-affected harmful factors are reduced, but measurement precision of fetal chromosomal abnormalities deteriorates
Solution Approach 1:
The patent replaces mechanical and biochemical screening methods (ultrasound measurements, hormone level testing) with direct genetic analysis. Instead of inferring chromosomal status indirectly through physical measurements or hormone levels, the method directly sequences fetal DNA to detect chromosomal abnormalities, achieving high precision while maintaining the non-invasive advantage
Solution Approach 2:
The patent changes the diagnostic parameter from indirect proxies (hormone levels, ultrasound measurements) to direct genetic information (fetal DNA sequence). By analyzing the actual genetic material rather than surrogate markers, the method achieves superior detection accuracy for chromosomal abnormalities while remaining non-invasive
3Measurement precision
If preferential enrichment at polymorphic loci is performed before sequencing, then measurement precision of allele counts is improved, but device complexity and processing time increase
Solution Approach 1:
The patent segments the genome into specific regions of interest (polymorphic loci) and applies preferential enrichment only to these segments rather than sequencing the entire genome. This targeted approach improves allele count precision by concentrating sequencing depth on informative regions while reducing overall complexity and processing requirements compared to whole-genome sequencing
Data Source
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AI summary
The present disclosure provides methods for determining the ploidy status of a chromosome in a gestating fetus from genotypic data measured from a mixed sample of DNA comprising DNA from both the mother of the fetus and from the fetus, and optionally from genotypic data from the mother and father. The ploidy state is determined by using a joint distribution model to create a plurality of expected allele distributions for different possible fetal ploidy states given the parental genotypic data, and comparing the expected allelic distributions to the pattern of measured allelic distributions measured in the mixed sample, and choosing the ploidy state whose expected allelic distribution pattern most closely matches the observed allelic distribution pattern. The mixed sample of DNA may be preferentially enriched at a plurality of polymorphic loci in a way that minimizes the allelic bias, for example using massively multiplexed targeted PCR.