Fetal Zygosity Determination Using Maternal DNA Reference

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Solution Overview

Problem

Current non-invasive prenatal diagnosis methods face challenges in accurately determining fetal zygosity for genetic diseases, especially when the mother is heterozygous, as they struggle to differentiate between homozygous and heterozygous scenarios, and are limited by the use of polymorphism sequences from homozygous mothers, reducing sensitivity and efficiency.

Innovation Solution

The method involves obtaining mother-only cellular DNA and mixed cfDNA from the mother, applying indexes to distinguish between maternal and fetal DNA, and sequencing to determine the presence and abundance of specific alleles, allowing for reliable estimation of fetal fraction and zygosity, including cases where the mother is heterozygous, using techniques like massively parallel sequencing and whole genome amplification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional non-invasive prenatal diagnosis methods are used, then the procedure is non-invasive and safe, but the ability to differentiate fetal zygosity is insufficient especially when the mother is heterozygous

Engineering Contradiction:

Improvediagnostic accuracyVSAvoidmethod complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the DNA analysis by separating maternal cellular DNA from fetal cfDNA through distinct extraction and processing pathways. Maternal DNA is extracted from isolated maternal cells while fetal DNA is analyzed from cell-free plasma, allowing independent analysis of each source to resolve zygosity ambiguities

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces an intermediary approach by using maternal cellular DNA as a reference baseline to interpret fetal cfDNA sequences. This intermediary reference enables differentiation of fetal homozygous vs heterozygous states by comparing against the known maternal genotype

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If only polymorphism sequences from homozygous mothers are used, then the analysis is simplified, but the sensitivity and efficiency of diagnosis are reduced

Engineering Contradiction:

Improvezygosity determination precisionVSAvoiddiagnostic efficiency

Core Design Contradiction:

Measurement precisionVSProductivity

Solution Approach 1:

The patent creates a universal diagnostic method that functions for all maternal zygosity states (homozygous and heterozygous). The same sequencing and analysis protocol can be applied regardless of maternal genotype, eliminating the need to restrict testing to homozygous mothers and thereby improving both precision and efficiency

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Quantity of substance

If invasive procedures are used to obtain fetal cells, then sufficient fetal genetic material is obtained for analysis, but the procedure carries risks to the fetus

Engineering Contradiction:

Improvefetal DNA quantityVSAvoidprocedural risk

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent uses maternal plasma as an intermediary medium to access fetal DNA without direct fetal sampling. Fetal cfDNA naturally circulates in maternal plasma, allowing retrieval of fetal genetic material through a simple blood draw from the mother, eliminating invasive procedures while maintaining diagnostic capability

Inventive Principle:

Principle #24Intermediary (Mediator)

4Loss of information

If maternal and fetal DNA are analyzed together without distinction, then the workflow is simplified, but the ability to determine fetal zygosity is compromised

Engineering Contradiction:

Improvefetal-specific genetic informationVSAvoidDNA analysis complexity

Core Design Contradiction:

Loss of informationVSDevice complexity

Solution Approach 1:

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality control by treating maternal and fetal DNA differently in the analysis pipeline. Maternal cellular DNA serves as a reference with known heterozygosity status, while fetal cfDNA is the target of investigation, with each processed and interpreted according to its specific characteristics

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS11629378B2Non-invasive prenatal diagnosis of fetal genetic condition using cellular DNA and cell free DNA

Publication Date: 2023.04.18 ILLUMINA INC

AI summary

Disclosed are methods for determining at least one sequence of interest of a fetus of a pregnant mother. In various embodiments, the method can determine one or more sequences of interest in a test sample that comprises a mixture of maternal cellular DNA and mother-and-fetus cfDNA. In some embodiments, methods are provided for determining whether the fetus has a genetic disease. In some embodiments, methods are provided for determining whether the fetus is homozygous in a disease causing allele when the mother is heterozygous of the same allele. In some embodiments, methods are provided for determining whether the fetus has a copy number variation (CNV) or a non-CNV genetic sequence anomaly.