Enriching Small Nucleic Acids for Prenatal Testing
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Solution Overview
Problem
Current non-invasive prenatal testing methods face challenges in detecting fetal aneuploidy due to the low concentration and small size of cell-free fetal DNA (cffDNA) in maternal plasma, making it difficult to distinguish subtle differences in DNA content between euploid and trisomic pregnancies.
Innovation Solution
The technology selectively enriches small cell-free circulating fetal nucleic acids, such as cffDNA, from maternal plasma by exploiting differences in DNA size distribution, using methods like silica-based capture, methylated DNA immunoprecipitation, and size exclusion, to increase the concentration and facilitate detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If direct chromosome enumeration methods are used to detect fetal aneuploidy, then non-invasive prenatal testing can be performed, but the low concentration of cffDNA makes it difficult to distinguish subtle differences in DNA content between euploid and trisomic pregnancies
Solution Approach 1:
The patent extracts and enriches small nucleic acid fragments (less than 200 bp) from maternal plasma that contain fetal DNA, separating them from larger maternal DNA fragments. This extraction process concentrates the target fetal DNA molecules, enabling more reliable detection of subtle chromosomal abnormalities by increasing the proportion of fetal DNA available for analysis.
Solution Approach 2:
The patent changes the size parameter threshold for DNA fragment selection, focusing specifically on small nucleic acid fragments less than 200 base pairs. This parameter change exploits the biological fact that fetal DNA fragments are smaller on average than maternal DNA fragments, thereby improving the ability to distinguish fetal from maternal DNA and enhancing measurement precision for aneuploidy detection.
2Measurement precision
If small nucleic acid enrichment is performed to improve detection sensitivity, then discrimination between euploid and aneuploid ratios is enhanced, but the processing complexity and time are increased
Solution Approach 1:
The patent performs preliminary enrichment of small nucleic acid fragments before the actual chromosomal analysis. By pre-concentrating fetal DNA molecules in the size range of less than 200 bp, the subsequent chromosome enumeration and aneuploidy detection require fewer statistical samples, thereby reducing the overall processing time despite the added enrichment step.
Solution Approach 2:
The patent uses next-generation sequencing to generate multiple copies (sequence reads) of the small nucleic acid fragments. This copying process amplifies the signal from the enriched fetal DNA, improving statistical power and detection sensitivity without requiring proportional increases in sample processing time, as the sequencing occurs in parallel high-throughput fashion.
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 enrichment method reduces the statistical burden of chromosome enumeration, improves sensitivity and throughput, and enables more confident discrimination between euploid and aneuploid ratios, leading to faster and more accurate prenatal testing results.
Implementation Method 1
silica-based capture
Implementation Method 2
methylated DNA immunoprecipitation
Implementation Method 3
size exclusion
Data Source
AI summary
Provided herein is technology related to processing samples of nucleic acids and particularly, but not exclusively, to methods for enriching samples for small nucleic acids, such as small circulating cell-free DNA.