Carrier-Only Haplotype Construction for Proband-Free Embryo Screening
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Solution Overview
Problem
Existing preimplantation genetic testing (PGT) methods for monogenic disorders and structural rearrangements rely on probands or reference individuals, which are not available in unique family structures or due to de novo mutations, limiting their applicability, especially in cases of consanguineous marriages with large homozygous regions.
Innovation Solution
A haplotype construction method that sequences only one chromosome abnormality carrier, obtaining pathogenic site and flanking sequence information through long fragment sequencing, enabling pathogenic/normal haplotype construction without relying on probands, using SNP screening and phasing for embryo analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If family-based linkage haplotype analysis is used, then the accuracy of preimplantation genetic testing is improved, but the method cannot be applied when no proband or reference individuals are available
Solution Approach 1:
The patent extracts the essential function of haplotype construction by sequencing only the pathogenic variation carrier parent, eliminating the requirement for probands or reference individuals. This extraction allows the system to function independently in unique family structures where traditional family-based analysis is not possible.
Solution Approach 2:
The patent introduces long fragment sequencing as an intermediary technology that enables haplotype construction without direct family member samples. The long fragment sequencing data serves as a mediator to infer pathogenic haplotypes in the absence of proband or reference samples.
2Reliability
If conventional PGT methods are used, then pathogenic variants can be detected in embryos, but the method fails in cases of de novo mutations or consanguineous marriages with large homozygous regions
Solution Approach 1:
The patent changes the fundamental parameter of sample requirement from multiple family members to a single pathogenic variation carrier parent. This parameter change enables the method to handle de novo mutations and consanguineous marriages where traditional multi-sample approaches fail.
Solution Approach 2:
The patent creates a universal haplotype construction method that works across different family structures including unique family structures, de novo mutations, and consanguineous marriages. The single-parent sequencing approach provides multi-functional applicability across these diverse scenarios.
3Measurement precision
If proband or reference samples are required for haplotype construction, then accurate pathogenic allele distinction is achieved, but the method becomes inapplicable when such samples are unavailable
Solution Approach 1:
The patent extracts and eliminates the requirement for proband or reference samples from the haplotype construction process. By sequencing only the pathogenic variation carrier parent, the system achieves pathogenic allele distinction without needing additional family member samples, significantly simplifying the operational requirements.
Data Source
AI summary
Disclosed is a haplotype construction method independent of a proband, comprising: performing long fragment sequencing on a DNA sample of one of pathogenic variation carrier parents in a couple; performing whole genome analysis on sequencing data of the pathogenic variation carrier parent to obtain genotype information of the pathogenic variation; screening heterozygous SNPs in the pathogenic variation carrier parent; gathering the heterozygous SNPs for whole genome assembly and typing; according to assembly information of the long fragment where the pathogenic variation is located, obtaining a typing result of the pathogenic variation site; and marking the haplotype of the pathogenic variation carrier parent according to the typing result of the pathogenic site, and constructing a pathogenic/normal haplotype of the pathogenic variation carrier parent. In the present application, only a pathogenic chromosome variation carrier is subjected to long fragment sequencing, and a haplotype of the carrier is constructed. The method can be effectively applied to genetic screening, and accurate haplotyping of the whole chromosome can be realized by means of the SNP interlocking analysis and correction of embryos.