Targeted Genomic Capture for Accurate Non-Invasive Prenatal Testing
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Solution Overview
Problem
Current non-invasive prenatal testing (NIPT) methods face challenges in distinguishing fetal DNA from maternal DNA, particularly in detecting chromosomal abnormalities like trisomy 21, due to the limited amount of fetal DNA and high levels of maternal DNA, leading to complications in quantification and false positives/negatives.
Innovation Solution
A targeted approach using TArget Capture Sequences (TACS) to enrich for specific sequences of interest in maternal plasma samples, optimized for length, placement, and GC content, followed by hybridization, isolation, and sequencing, coupled with statistical analysis to accurately detect chromosomal abnormalities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If whole genome sequencing is used to detect fetal chromosomal abnormalities, then comprehensive genomic coverage is achieved, but sequencing costs and data complexity increase significantly
Solution Approach 1:
The patent extracts and sequences only specific chromosomal regions of interest (e.g., regions associated with aneuploidies) rather than performing whole genome sequencing. This is achieved through targeted enrichment methods that isolate and amplify only the relevant genomic segments, reducing sequencing complexity while maintaining detection accuracy for chromosomal abnormalities.
Solution Approach 2:
The genome is divided into specific segments or regions of interest that are relevant to chromosomal abnormality detection. The patent focuses sequencing efforts on these segmented regions rather than the entire genome, thereby reducing the overall complexity and cost while preserving the ability to detect abnormalities in critical chromosomal areas.
2Measurement precision
If targeted enrichment methods are used to increase fetal DNA proportion, then detection sensitivity improves, but false positives may increase due to enrichment biases
Solution Approach 1:
The patent incorporates normalization procedures that use feedback from control samples and reference data to correct for enrichment biases. By comparing enriched fetal DNA signals against expected baseline values and adjusting for technical variations, the method reduces false positives while preserving the enhanced sensitivity gained through targeted enrichment.
Solution Approach 2:
The patent optimizes enrichment parameters such as hybridization conditions, probe design, and amplification cycles to maximize fetal DNA recovery while minimizing bias. By carefully controlling these parameters, the method achieves high sensitivity without introducing significant artifacts that would lead to false positive results.
3Measurement precision
If more sequencing depth is applied to detect low-abundance fetal DNA, then quantification accuracy improves, but sequencing costs and time increase
Solution Approach 1:
The patent extracts and enriches fetal DNA from maternal plasma samples using targeted capture methods before sequencing. This pre-enrichment step concentrates the low-abundance fetal DNA, allowing for accurate quantification at lower sequencing depths compared to direct sequencing of total cell-free DNA, thereby reducing costs and increasing throughput.
Solution Approach 2:
The patent performs preliminary enrichment and concentration of fetal DNA through targeted capture and amplification steps before the actual sequencing process. This preliminary action ensures that sufficient fetal DNA is available for accurate quantification, eliminating the need for excessive sequencing depth and associated costs.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Reduces sequencing requirements, enhances accuracy, and lowers costs while providing high-throughput analysis for detecting chromosomal abnormalities such as aneuploidies and structural abnormalities with minimal false positives/negatives.
Implementation Method 1
hybridizing the sequencing library to a pool of TArget Capture Sequences (TACS)
Data Source
AI summary
The invention provides methods for non-invasive prenatal testing that allow for detecting risk of chromosomal and subchromosomal abnormalities, including but not limited to aneuploidies, microdeletions and microduplications, insertions, translocations, inversions and small-size mutations including point mutations and mutational signatures. The methods of the invention utilize a pool of TArget Capture Sequences (TACS) to enrich for sequences of interest in a mixed sample containing both maternal and fetal DNA, followed by massive parallel sequencing and statistical analysis of the enriched population to thereby detect the risk of a genetic abnormality in the fetal DNA. Kits for carrying out the methods of the invention are also provided.