Clinical application of an Asian Screening Array-based preimplantation genetic testing workflow for various genetic disorders

Preimplantation genetic testing for monogenic disorders (PGT-M) represents a critical clinical strategy for preventing the transmission of hereditary diseases from carriers to offspring, with its diagnostic efficacy heavily dependent on the accuracy and coverage of detection platforms. Genome-wide SNP array such as the Asian Screening Array (ASA), has demonstrated favorable performance in haplotype analysis for PGT-M. Here, we systematically evaluated the efficiency of the Asian Screening Array-based PGT workflow in PGT application for different genetic disorders.

We conducted a retrospective analysis by reviewing 377 pedigrees underwent PGT-M preclinical work-up and 367 PGT-M clinical cycles (1677 embryos in total) based on the Asian Screening Array. We established detection strategies combining ASA haplotyping analysis and individualized direct mutation detection based on different genetic patterns. Long-read sequencing or single-sperm haplotyping strategy was applied for families with de novo pathogenic variants or lacking family member samples. Individualized direct mutation detection methods such as Gap-PCR, RP-PCR, PCR-RFLP were adopted for different cases.

Results indicated the clinical validity of our ASA-based PGT workflow, integrating linkage analysis, direct mutation detection, and chromosomal CNV screening. The number of SNPs available for linkage analysis in the upstream and downstream regions of target genes/regions is sufficient for most of the cases. Individualized direct mutation detection methods for different cases also validated the ASA haplotyping results. In haplotype analysis, the method based on long-read sequencing is more effective than single-sperm haplotyping strategy. Detailed haplotyping strategy for families with microdeletions and tandem duplications was established based on ASA. A total of 636 embryos were ultimately deemed suitable for transfer after undergoing linkage analysis and CNV detection.

This study validated the feasibility and superiority of ASA-based approach in PGT, also provided a standardized and reliable technical solution for the clinical prevention of different genetic disorders.