Multiplexed Ligation Assay for Noninvasive Prenatal Genetic Screening

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Solution Overview

Problem

Current prenatal diagnostic methods for genetic abnormalities require invasive procedures and multiple tests to detect chromosomal aneuploidy and single gene disorders, posing risks and inefficiencies, especially in identifying genetic variations in mixed samples like maternal-fetal DNA.

Innovation Solution

The development of multiplexed sequential ligation-based analysis methods using oligonucleotide probes for sequential hybridization, elongation, ligation, and amplification to accurately detect chromosomal abnormalities, copy number variations, and polymorphisms from a single sample, allowing for simultaneous analysis of multiple genomic regions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional prenatal diagnostic methods are used to detect chromosomal aneuploidy and single gene disorders, then diagnostic information can be obtained, but invasive procedures are required which carry miscarriage risk

Engineering Contradiction:

Improvediagnostic accuracyVSAvoidmiscarriage risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention extracts and analyzes only the necessary genetic information from circulating fetal DNA in maternal blood, rather than requiring extraction of fetal cells through invasive procedures. This allows diagnostic information to be obtained from a simple blood draw, eliminating the physical trauma and miscarriage risk associated with chorionic villus sampling or amniocentesis while maintaining diagnostic accuracy for chromosomal aneuploidy and single gene disorders

Inventive Principle:

Principle #2Taking out (Extraction)

2Adaptability or versatility

If multiple separate tests are performed to detect different types of genetic abnormalities, then comprehensive genetic information can be obtained, but the complexity and number of procedures increases

Engineering Contradiction:

Improvecomprehensive genetic coverageVSAvoidnumber of tests

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The invention merges multiple diagnostic capabilities into a single integrated assay that simultaneously detects chromosomal aneuploidy (such as trisomies 13, 18, and 21) and single gene disorders (such as cystic fibrosis, sickle cell anemia, and Tay-Sachs disease) from the same maternal blood sample. This consolidation eliminates the need for separate invasive procedures for each type of genetic testing, reducing procedural complexity while maintaining comprehensive genetic coverage

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The diagnostic method achieves multi-functionality by using a universal approach that can detect multiple classes of genetic abnormalities through a single procedure. The assay is designed to simultaneously interrogate both chromosomal-level abnormalities and gene-level mutations using circulating fetal DNA, making the test universally applicable for comprehensive prenatal genetic screening without requiring multiple specialized tests

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Loss of information

If conventional methods are used to analyze fetal DNA, then chromosomal abnormalities can be detected, but information about single gene traits is not provided

Engineering Contradiction:

Improvesingle gene informationVSAvoidtesting requirements

Core Design Contradiction:

Loss of informationVSDevice complexity

Solution Approach 1:

The invention performs preliminary enrichment and selection of circulating fetal DNA from maternal blood before analysis. This preliminary action concentrates the fetal genetic material and removes maternal DNA background, enabling subsequent simultaneous detection of both chromosomal abnormalities and single gene mutations without requiring separate invasive procedures for each type of genetic information

Inventive Principle:

Principle #10Preliminary action

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 enhances the accuracy and fidelity of genetic information by enabling the detection of various genetic anomalies from a single sample with reduced invasiveness and the ability to analyze multiple regions simultaneously, improving prenatal diagnostic efficiency.

Implementation Method 1

sequential hybridization, elongation (optional), ligation and amplification reactions of an initial set of oligonucleotide probes and of at least one subsequent set of oligonucleotide probes in the same locus or region of interest

Methodology Applied

Scientific EffectHybridization:

Implementation Method 2

sequential hybridization, elongation (optional), ligation and amplification reactions of an initial set of oligonucleotide probes

Methodology Applied

Scientific EffectElongation:

Implementation Method 3

sequential hybridization, elongation (optional), ligation and amplification reactions of an initial set of oligonucleotide probes

Methodology Applied

Scientific EffectLigation:

Implementation Method 4

sequential hybridization, elongation (optional), ligation and amplification reactions of an initial set of oligonucleotide probes and of at least one subsequent set of oligonucleotide probes

Methodology Applied

Scientific EffectAmplification:

Data Source

PatentUS9624490B2Multiplexed sequential ligation-based detection of genetic variants

Publication Date: 2017.04.18 ROCHE MOLECULAR SYSTEMS INC

AI summary

The present invention provides multiplexed sequential ligation-based analysis of genetic variants in a mixed sample, including copy number variations and single nucleotide polymorphisms. The invention employs the techniques of sequential ligation and amplification.