Target Capture Sequences for Prenatal Genetic Risk Assessment
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Solution Overview
Problem
Current Non-Invasive Prenatal Testing (NIPT) methods face challenges in detecting fetal genetic abnormalities due to the limited amount of free fetal DNA in maternal circulation, requiring more extensive sequencing and struggling to identify low signal-to-noise ratio regions, and lack methods for assessing both fetal genetic aberrations and inherited genetic conditions simultaneously.
Innovation Solution
The development of multiplexed parallel sequencing methods using Target Capture Sequences (TACS) that enrich specific genomic regions, allowing for the assessment of fetal risk of inherited genetic conditions by determining maternal and paternal carrier status, and identifying genetic abnormalities such as chromosomal aneuploidy through hybridization, amplification, and statistical analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If massively parallel shotgun sequencing (MPSS) is used to analyze the entire maternal sample, then comprehensive genomic coverage is achieved, but the sequencing cost and complexity increase significantly
Solution Approach 1:
The patent extracts and enriches only the specific genomic regions of interest from the entire maternal sample using hybridization capture technology. This allows focused sequencing on targeted loci associated with genetic conditions, achieving comprehensive coverage of relevant regions while avoiding the need to sequence the entire genome, thus reducing sequencing complexity and cost.
Solution Approach 2:
The patent segments the genomic analysis into specific targeted regions rather than analyzing the entire genome uniformly. By dividing the genomic landscape into discrete loci of interest and using probe-based enrichment, the method achieves precise measurement of relevant regions while simplifying the overall sequencing process.
2Productivity
If targeted-based NGS approaches are used to sequence only specific loci, then sequencing cost is reduced, but the read-depth in low signal-to-noise ratio regions decreases
Solution Approach 1:
The patent performs preliminary enrichment of target sequences through hybridization capture before sequencing. This preliminary action concentrates the fetal DNA fragments containing variants of interest, increasing their read-depth and signal-to-noise ratio, thereby improving detection sensitivity while maintaining sequencing efficiency.
3Adaptability or versatility
If the entire maternal sample is sequenced, then all genetic conditions can be detected, but the amount of sequencing required increases
Solution Approach 1:
The patent creates a universal hybridization capture platform that can detect multiple different genetic conditions by simply changing the probe set. The same enrichment methodology can be applied to detect various inherited genetic conditions, chromosomal abnormalities, and other genetic variations, providing multi-functionality without requiring separate sequencing approaches for each condition.
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
This approach significantly reduces sequencing needs, increases read-depth in regions of interest, and enables reliable detection of genetic aberrations present in small amounts, allowing for simultaneous assessment of fetal genetic risks and abnormalities in a single sample.
Implementation Method 1
hybridizing the sequencing library to a pool of double-stranded TArget Capture Sequences (TACS), wherein the pool of TACS comprises a plurality of sequences that bind to genomic regions of interest including variant allele loci of interest
Implementation Method 2
amplifying and sequencing the enriched library
Data Source
AI summary
The invention provides methods for assessment of risk for genetic conditions using target-enriched multiplexed parallel analysis, for example fetal risk for genetic conditions in prenatal testing. The methods of the invention utilize TArget Capture Sequences (TACS) to thereby enrich for target sequences of interest, followed by massive parallel sequencing and statistical analysis of the enriched population. The methods of the disclosure can be used to determine carrier status of inheritable genetic abnormalities associated with genetic conditions and from this information the fetal risk of inheriting the genetic condition can be determined. Kits for carrying out the methods of the invention are also provided.