Analysis Of Embryonic Euploid Rate Of Couples Receiving Preimplantation Genetic Testing For Monogenic Disease

Background:Monogenic disease is the main pathogeny of birth defects.It affects millions of people around the world,and nearly 900 thousand new babies with birth defects are born in China every year,among whom the monogenic disease accounts for nearly 5%.According to OMIM,more than 8,000 diseases have been officially catalogued.With the widespread use of whole exome sequencing and development of data analysis strategies,the genetic diagnosis rates of monogenic disease have been improved.Although fetuses with pathogenic mutations can be identified by prenatal diagnosis with amniocentesis,induced abortion of mid-trimester pregnancy gives rise to physical and psychological trauma to the women.With the development of assist reproductive technologies,the Preimplantation Genetic Testing for Monogenic Disease(PGT-M)has become a prioritized choice,for the patients undergoing PGT-M,their blastocysts are additionally tested for euploidy,aiming to increase the live birth rate and reduce the risk of miscarriage and birth defects related to chromosome abnormalities.Considering many genes causative for monogenic disease influence mitosis and genome stability,the euploidy rate of blastocysts might be affected by the monogenic disorders as well.However,the relationship between monogenic disease and embryo euploidy is still unclear.Therefore,in the present study,we made a pilot study to answer the question and provide an important reference for clinicians to conduct genetic counseling for couples with monogenic diseases.Methods:In the present study,242 cycles with PGT-M treatment in Reproductive Hospital affiliated to Shandong University from 2017 to 2020 were recruited in the PGT-M group.The PGT-A cycles were recruited as control,we got the 603 patients with 603 PGT-A cycles from a multicenter randomized controlled trial(RCT)Euploid rates were compared between PGT-M and PGT-A patients in different aging subgroups.Generalized estimating equation(GEE)was used to control repeated cycles and confounding factors,including age,BMI,FSH,and AMH.To further explore the effects of different monogenic diseases on blastocyst euploidy,the PGT-M group was divided into autosomal and sex chromosomes group for analysis based on the type of chromosomes where the monogenetic mutation localized.To elucidate whether the common monogenic diseases affected the euploid rate,four diseases with relatively high incidence were also further analyzed.Results:We compared the euploidy rate between PGT-M and PGT-A group,and found it was significantly lower in the PGT-M group(52.4%vs 69.7%,P<0.001).Considering the age,BMI,FSH and AMH were confounding factors for euploidy formation,we adjusted them by generalized estimating equation.Then,we found that patients underwent PGT-M still had a lower rate to obtain euploidy compared with women received PGT-A after adjusting those confounding.(OR:0.556,95%CI:0.456-0.677;P<0.001).we separated the patients into three subgroups according to age,and found the patients receiving PGT-M in individual subgroups also presented lower euploidy rate(40.0%vs 67.4%,P<0.001;54.5%vs71.2%,P<0.001).Moreover,we observed that the euploidy rate of couples with the four gene mutations(SBDS,LMNA,MECP2 and RBI)was lower than that of PGT-A(48%vs 69.7%,P=0.02).After adjusting confounding factors by Logistics,the euploid rate of two groups did not reach statistical significance(OR:2.15;95%CI:0.961-4.808,P-adj=0.062).Interestingly,although there was no difference in age between patients with polycystic kidney or methylmalonic acidemia and PGT-A group,significantly lower percentage of blastocyst euploid was still identified in couples with the two diseases(46.0%vs 69.7%,P<0.001;53.5%vs 69.7%,P<0.001).Conclusion:Through the pilot study,we found a lower incidence of euploid embryos in couples with monogenic disease,who receiving PGT-M treatment.After adjustment of age and measures of diminished ovarian reserve,the genetic defects causing monogenic diseases still presented to be a risk factor for embryo aneuploidy.Moreover,polycystic kidney or methylmalonic acidemia have been found to affect the euploid rate of embryo independent of female age,which should be confirmed in the further studies.