Robertsonian Translocation Detection via Haplotype Analysis
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Solution Overview
Problem
Current methods for detecting chromosomal Robertsonian translocation in embryos and abortion tissues during test-tube baby technology are limited by high false negative rates and inability to differentiate between normal and translocation-carrying embryos, leading to missed diagnoses and increased risk of pregnancy complications.
Innovation Solution
A method utilizing high-throughput sequencing technology to screen for hypermutational SNP sites near the centromere of acrocentric chromosomes, analyzing chromosome copy numbers, and determining genotypes and haplotypes to accurately detect chromosomal Robertsonian translocations in embryos and abortion tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If SNP chip technology is used for preimplantation genetic diagnosis, then the detection process is simplified and high-throughput sequencing can be performed, but the method cannot differentiate normal embryos from translocation-carrying embryos, resulting in false negative rates
Solution Approach 1:
The invention divides the detection process into two independent stages: first, SNP chip technology is used for high-throughput detection of chromosome copy numbers; second, targeted sequencing is applied to specific hypermutational SNP sites near centromeres to determine haplotypes. This segmentation allows each method to发挥 its strengths while overcoming individual limitations, resolving the contradiction between throughput and precision.
Solution Approach 2:
The invention introduces haplotype analysis as an intermediary step between copy number detection and final diagnosis. By using hypermutational SNP sites as markers and analyzing haplotype combinations, the method creates an intermediate layer of information that enables precise differentiation of translocation-carrying embryos from normal ones, while still building upon the high-throughput SNP chip data.
2Measurement precision
If FISH technology is used to examine single nucleus, then chromosomal translocation can be detected, but the method has a 7% false negative rate and cannot examine multiple nuclei efficiently
Solution Approach 1:
The invention makes the detection method universally applicable to multiple nuclei simultaneously by using DNA extraction and high-throughput sequencing technology. Unlike FISH which requires individual nucleus examination, this method can process multiple embryos in parallel, achieving both high accuracy through comprehensive analysis and high productivity through automation and multiplexing.
Solution Approach 2:
The invention replaces the mechanical FISH procedure (hybridization, washing, microscopy) with a biochemical-DNA-based system involving DNA extraction, library preparation, and sequencing. This substitution eliminates the limitations of FISH while maintaining or improving detection accuracy, and enables automated high-throughput processing.
3Productivity
If SNP chip technology is used for detection, then high-throughput sequencing is enabled, but the method cannot differentiate normal embryo from translocation carrying embryo
Solution Approach 1:
The invention performs preliminary action by first identifying hypermutational SNP sites near centromeres of acrocentric chromosomes and establishing haplotype patterns in parental carriers before actual embryo diagnosis. This preliminary characterization of translocation-specific haplotypes enables accurate differentiation during the high-throughput sequencing phase, ensuring both efficiency and reliability.
Solution Approach 2:
The invention adds another dimension to the detection by moving from single-locus copy number analysis to multi-locus haplotype analysis. By examining combinations of SNP alleles across multiple hypermutational sites, the method creates a higher-dimensional diagnostic space that can distinguish translocation-carrying embryos from normal ones, overcoming the limitations of one-dimensional SNP chip data.
Data Source
AI summary
Provided is a method for detecting chromosomal Robertsonian translocation and the SNP (single nucleotide polymorphism) site and primer composition for use therein. The method is practical, simple, convenient and high in universality; moreover, a high-throughput sequencing technology is combined, so that the method has the advantages of low cost, and high sensitivity, specificity and accuracy.