Preimplantation genetic testing for type 2 diabetes based on family-specific polygenic risk score: A proof-of-concept...

This study aims to evaluate the feasibility of family-specific polygenic risk prediction in reducing the risk of type 2 diabetes (T2D) in the offspring from an infertile couple with a family history of early-onset T2D.

We innovatively established a family-specific polygenic risk prediction model for this T2D family and the embryo with the lowest risk of T2D were selected for implantation.

Initially, whole exome sequencing analysis in the family failed to identify monogenic-level pathogenic or likely pathogenic variants responsible for T2D. Thus, preimplantation genetic testing for monogenic disease (PGT-M) may be not applicable. Subsequently, we innovatively developed a family-specific polygenic-level T2D risk prediction model including 114 T2D risk SNPs and weighted by the genotype-phenotype correlation of asymptomatic individuals and T2D patients in the pedigree. Using this model, the euploid embryo P_5977_1C exhibited the lowest T2D risk and was selected for implantation. The newborn displayed the same lowest T2D polygenic risk and normal growth and development after a 16-month follow-up.

Our study provided preliminary evidence for the feasibility of developing a more accurate polygenic risk prediction model using pedigree information and its application in embryo selection.