Massively Parallel Genomic Sequencing for Fetal Aneuploidy Detection

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Solution Overview

Problem

Conventional prenatal diagnostic methods for fetal chromosomal aneuploidy, such as trisomy 21, face challenges including invasive procedures with fetal loss risk, suboptimal accuracy of non-invasive methods, interference from maternal nucleic acids, and limitations in detecting fetal nucleic acids in maternal plasma.

Innovation Solution

A method involving sequencing a fraction of nucleic acid molecules from a biological sample, determining the amounts of clinically relevant and background chromosomal regions, and comparing these amounts to cutoff values to classify fetal chromosomal aneuploidy using random sequencing and bioinformatics analysis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If invasive procedures such as amniocentesis or chorionic villus sampling are used to diagnose fetal chromosomal aneuploidy, then diagnostic accuracy is improved, but the risk of fetal loss increases

Engineering Contradiction:

Improvediagnostic accuracyVSAvoidfetal loss risk

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The invention extracts and analyzes cell-free fetal DNA molecules from maternal plasma, separating the diagnostic target (fetal DNA) from the invasive procedure requirement. By detecting fetal-specific nucleic acid sequences in the maternal circulation, the method obtains chromosomal dosage information without physical intrusion into the fetus, thereby maintaining high diagnostic accuracy while eliminating fetal loss risk

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention uses cell-free fetal DNA in maternal plasma as an intermediary carrier of chromosomal information. Instead of directly sampling fetal cells through invasive procedures, the method detects chromosomal dosage via fetal DNA molecules that naturally circulate in maternal plasma, serving as a non-invasive mediator for prenatal diagnosis

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If non-invasive screening methods such as ultrasonography and biochemical markers are used, then fetal loss risk is reduced, but diagnostic accuracy deteriorates

Engineering Contradiction:

Improvefetal loss riskVSAvoiddiagnostic accuracy

Core Design Contradiction:

Object-affected harmful factorsVSMeasurement precision

Solution Approach 1:

The invention replaces mechanical and biochemical screening methods (ultrasonography, serum marker measurement) with molecular genetic analysis. By using massively parallel genomic sequencing to directly detect chromosomal dosage from fetal DNA sequences in maternal plasma, the method substitutes indirect phenotypic screening with direct genotypic analysis, achieving high diagnostic accuracy through non-invasive means

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The invention changes the detection parameter from indirect biochemical markers to direct chromosomal sequence dosage. Instead of measuring epiphenomena associated with aneuploidy, the method quantifies the actual number of fetal chromosomal sequences in maternal plasma, providing a more accurate and direct measure of chromosomal status

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If fetal-specific nucleic acids are detected in maternal plasma, then maternal background interference is overcome, but the amount of fetal nucleic acid available for analysis is limited

Engineering Contradiction:

Improvesignal-to-noise ratioVSAvoidamount of fetal nucleic acid

Core Design Contradiction:

Measurement precisionVSQuantity of substance

Solution Approach 1:

The invention segments the analysis into two distinct phases: first, enrichment of fetal-specific nucleic acid sequences from the mixed maternal-fetal plasma sample using targeted capture methods; second, massively parallel sequencing of the enriched material. This segmentation allows efficient use of limited fetal DNA by concentrating it before analysis, overcoming both the background interference and the quantity limitation

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention employs a universal massively parallel sequencing platform that can analyze multiple chromosomal targets simultaneously from a single enriched fetal DNA sample. This multi-functional approach maximizes the information obtained from limited fetal nucleic acid by detecting copy number variations across numerous chromosomal regions in one assay

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250320558A1Diagnosing fetal chromosomal aneuploidy using massively parallel genomic sequencing

Publication Date: 2025.10.16 THE CHINESE UNIVERSITY OF HONG KONG

AI summary

Embodiments of this invention provide methods, systems, and apparatus for determining whether a fetal chromosomal aneuploidy exists from a biological sample obtained from a pregnant female. Nucleic acid molecules of the biological sample are sequenced, such that a fraction of the genome is sequenced. Respective amounts of a clinically-relevant chromosome and of background chromosomes are determined from results of the sequencing. A parameter derived from these amounts (e.g. a ratio) is compared to one or more cutoff values, thereby determining a classification of whether a fetal chromosomal aneuploidy exists.