Preimplantation Genetic Testing for Kidney Disease-Related Genes: A Laboratory's Experience.

INTRODUCTION: Recent literature highlights the clinical utility of genetic testing for patients with kidney disease. Genetic testing provides significant benefits for reproductive risk counseling, including the option of in vitro fertilization with preimplantation genetic testing for monogenic disease (PGT-M). PGT-M allows for a significant reduction in risk for a pregnancy affected with the familial disease. We aim to summarize our experience with PGT-M for genes with kidney involvement as either a primary or secondary feature of the disease. METHODS: All PGT-M tests performed by the reference laboratory between September 2010 and July 2020 were reviewed for clinical indication and cases for which the disease tested included a renal component. Each patient referred for PGT-M had an existing molecular genetic diagnosis themselves or in their family. Frequency of each condition, gene, inheritance pattern, and year over year increase in referral cases was analyzed. RESULTS: In the study cohort, the most common disease targeted was autosomal dominant polycystic kidney disease, caused by pathogenic variants in the PKD1 or PKD2 genes, which accounted for 16.5% (64/389) of cases. The 5 most common referral indications accounted for 51.9% (202/389) of the cases. Autosomal recessive inheritance accounted for 52.0% (26/50) of conditions for which PGT-M was performed. The number of PGT-M tests performed for conditions that included either primary or secondary kidney disease increased from 5 cases in 2010 to 47 cases in the 2020 study period. DISCUSSION/CONCLUSION: These data suggest that the pursuit of PGT-M by couples at risk for passing on conditions with a kidney component is common and has significantly increased since 2010. With this rising trend of patients undergoing PGT-M and the prerequisite of molecular genetic confirmation in the PGT-M process, this study underscores the importance of the reproductive component to a molecular genetic diagnosis for patients with kidney disease, especially as the accessibility of genetic testing and utilization by nephrologists grows.

Whole genome prediction for preimplantation genetic diagnosis.

BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.

Pregnancy outcomes following 24-chromosome preimplantation genetic diagnosis in couples with balanced reciprocal or Robertsonian translocations.

OBJECTIVE: To report live birth rates (LBR) and total aneuploidy rates in a series of patients with balanced translocations who pursued in vitro fertilization (IVF)-preimplantation genetic diagnosis (PGD) cycles. DESIGN: Retrospective cohort analysis. SETTING: Genetic testing reference laboratory. PATIENT(S): Seventy-four couples who underwent IVF-PGD due to a parental translocation. INTERVENTION(S): IVF cycles and embryo biopsies were performed by referring clinics. Biopsy samples were sent to a single reference lab for PGD for the translocation plus 24-chromosome aneuploidy screening with the use of a single-nucleotide polymorphism (SNP) microarray. MAIN OUTCOME MEASURE(S): LBR per biopsy cycle, aneuploidy rate, embryo transfer (ET) rate, miscarriage rate. RESULT(S): The LBR per IVF biopsy cycle was 38%. LBR for patients reaching ET was 52%. Clinical miscarriage rate was 10%. Despite a mean age of 33.8 years and mean of 7 embryos biopsied, there was a 30% chance for no chromosomally normal embryos. Maternal age >35 years, day 3 biopsy, and having fewer than five embryos available for biopsy increased the risk of no ET. CONCLUSION(S): IVF-PGD for translocation and aneuploidy screening had good clinical outcomes. Patients carrying a balanced translocation who are considering IVF-PGD should be aware of the high risk of no ET, particularly in women ≥35 years old.