Chromosomal Quantification via Partially Homologous Markers
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Solution Overview
Problem
Current prenatal diagnosis methods, such as QF-PCR, face limitations in distinguishing homozygous and monosomic individuals, particularly for sex chromosome abnormalities, due to the need for heterozygous patterns and potential misdiagnosis in samples with maternal cell contamination or mosaicism, leading to inaccurate results.
Innovation Solution
The method employs at least two partially homologous marker sequences, one on the X chromosome and one on an autosomal chromosome, using PCR primer pairs to amplify and detect DNA fragments, allowing for a 2:1 ratio indicative of Turner's syndrome, thereby overcoming the limitations of previous techniques by enabling quantification regardless of homozygosity or heterozygosity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of time
If QF-PCR with chromosome-specific STR markers is used for rapid prenatal diagnosis, then diagnosis speed is improved (results within 48 hrs), but reliability deteriorates due to inability to distinguish homozygous from monosomic individuals
Solution Approach 1:
The patent segments the diagnostic approach by using multiple independent marker systems: traditional STR markers and novel SNPs with known allele frequencies. This segmentation allows cross-validation of results, where STR markers provide rapid initial assessment while SNP allele frequency analysis provides confirmatory evidence to distinguish homozygous from monosomic cases, thereby resolving the reliability issue without sacrificing speed
Solution Approach 2:
The patent changes the analytical parameter from relying solely on peak area ratios (which fail in homozygous cases) to incorporating SNP allele frequency distributions. By analyzing whether observed allele frequencies match expected population frequencies for heterozygous individuals, the system can identify homozygous cases and trigger alternative diagnostic pathways, thus maintaining rapid diagnosis while improving accuracy
2Measurement precision
If multiple X-chromosome STR markers are incorporated to reduce homozygosity likelihood, then measurement precision improves, but device complexity increases
Solution Approach 1:
The patent makes the diagnostic system universal by developing a platform that handles both heterozygous and homozygous cases through a unified approach. The SNP-based allele frequency analysis serves as a universal solution that works regardless of STR marker heterozygosity status, eliminating the need for complex case-by-case adjustments and reducing overall system complexity while maintaining high measurement precision
3Measurement precision
If heterozygous pattern detection is required for accurate QF-PCR results, then measurement precision improves, but adaptability deteriorates as the method fails in homozygous or monosomic samples
Solution Approach 1:
The patent introduces a dynamic diagnostic workflow that adapts based on initial STR marker results. When homozygosity is detected, the system dynamically switches to SNP allele frequency analysis to determine ploidy status. This dynamic adaptation allows the system to maintain high measurement precision across diverse genetic scenarios including heterozygous, homozygous, and monosomic cases, significantly improving versatility
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 provides accurate quantification of chromosomes and genes, reducing misdiagnosis and improving the detection of chromosomal aneuploidies and sex chromosome abnormalities, including Turner's syndrome, by using partially homologous marker sequences that distinguish amplification products based on size and sequence differences.
Implementation Method 1
Molecular methods based on Polymerase Chain Reaction (PCR) and DNA probe hybridisation have therefore been developed
Implementation Method 2
Molecular methods based on Polymerase Chain Reaction (PCR) and DNA probe hybridisation have therefore been developed
Data Source
AI summary
Diagnosis of chromosomal abnormalities or genetic disorders is performed using at least two marker sequences, wherein one marker sequence is a sequence known to be present on the chromosome or in the gene of interest, another marker sequence is a sequence known to be present on an autosomal chromosome, and the marker sequences are partially homologous. A kit for performing this diagnosis is also claimed.