The preimplantation genetic testing for monogenic disorders strategy for blocking the transmission of hereditary cancers through haplotype linkage analysis by karyomapping.

PURPOSE: Providing feasible preimplantation genetic testing strategies for monogenic disorders (PGT-M) for prevention and control of genetic cancers. METHODS: Inclusion of families with a specific pathogenic mutation or a clear family history of genetic cancers. Identification of the distribution of hereditary cancer-related mutations in families through genetic testing. After a series of assisted reproductive measures such as down-regulation, stimulation, egg retrieval, and in vitro fertilization, a biopsy of trophectoderm cells from a blastocyst was performed for single-cell level whole-genome amplification (WGA). Then, the detection of chromosomal aneuploidies was performed by karyomapping. Construction of a haplotype-based linkage analysis to determine whether the embryo carries the mutation. Meanwhile, we performed CNV testing. Finally, embryos can be selected for transfer, and the results will be verified in 18-22 weeks after pregnancy. RESULTS: Six couples with a total of 7 cycles were included in our study. Except for cycle 1 of case 5 which did not result in a transferable embryo, the remaining 6 cycles produced transferable embryos and had a successful pregnancy. Four couples have had amniotic fluid tests to confirm that the fetus does not carry the mutation, while 1 couple was not tested due to insufficient pregnancy weeks. And the remaining couples had to induce labor due to fetal megacystis during pregnancy. CONCLUSION: Our strategy has been proven to be feasible. It can effectively prevent transmission of hereditary cancer-related mutations to offspring during the prenatal stage.

Identification of carrier status of Xp22.31 microdeletions associated with X-linked ichthyosis at the single-cell level using haplotype linkage analysis by karyomapping.

PURPOSE: Currently, owing to the limitations of high-throughput sequencing depth and the allele dropout caused by the whole-genome amplification, detection of chromosomal variants in embryos with CNVs <5 Mb is unsatisfactory at the single-cell level using only conventional sequencing methods. Therefore, here we aimed to use a strategy of preimplantation genetic testing for monogenic (PGT-M) to compensate for the shortcomings of conventional sequencing methods. The purpose of this study is to report the effectiveness of haplotype linkage analysis by karyomapping for preimplantation diagnosis microdeletion diseases. METHODS: Six couples carrying chromosomal microdeletions associated with X-linked ichthyosis were recruited, and all couples entered the PGT process. Multiple displacement amplification (MDA) method was used to amplify the whole-genome DNA of trophectoderm cells. Then karyomapping based on single nucleotide polymorphism (SNP) was used for haplotype linkage analysis to detect alleles carrying microdeletions, and CNVs of embryos were identified to determine euploid identity. Amniotic fluid tests were performed in the second trimester to verify the PGT-M results. RESULTS: All couples were tested for chromosomal microdeletions, with deletion fragments ranging in size from 1.60 to 1.73 Mb, and one partner in each couple did not carry the microdeletion. Three couples successfully underwent PGT-M assisted conception and obtained healthy live births. CONCLUSION: This study shows that haplotype linkage analysis by karyomapping could effectively detect the carrier status of embryos with microdeletions at the single-cell level. This approach may be applied to the preimplantation diagnosis of various chromosomal microvariation diseases.

The risk of breast cancer and gynecologic malignancies after ovarian stimulation: Meta-analysis of cohort study.

The effects of ovarian stimulation on breast and gynecological tumor incidence remain controversial. Therefore, the aim of this meta-analysis was to study the risk of cancer in ovarian stimulation. Of the 22713 studies initially identified, 28 were eligible for inclusion. The results revealed that the impact of ovarian cancer (RR = 1.33, [1.05; 1.69]) and cervical cancer (RR = 0.67, [0.46; 0.97]) is significant among the overall effects. In subgroup analysis, in the nulliparous population (RR = 0.81 [0.68; 0.96]) was the protective factor for the breast cancer. In the Caucasians subgroup (RR = 1.45, [1.12; 1.88]), the ovarian cancer incidence was statistically significant. In the Asian subgroup (RR = 1.51, [1.00; 2.28]), the endometrial cancer incidence was statistically significant. In the subgroup of Asians (RR = 0.55 [0.44; 0.68]) and the multiparous population (RR = 0.31, [0.21; 0.46]), them can be the statistically protective factor for the cervical cancer.