Successful Combined Preimplantation Genetic Testing for Aneuploidy (PGT-A) and for Monogenic Disorders (PGT-M) for Autosomal Dominant Polycystic Kidney Disease Following Kidney Transplant: A Case Report

Successful Combined Preimplantation Genetic Testing for Aneuploidy (PGT-A) and for Monogenic Disorders (PGT-M) for Autosomal Dominant Polycystic Kidney Disease Following Kidney Transplant: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Successful Combined Preimplantation Genetic Testing for Aneuploidy (PGT-A) and for Monogenic Disorders (PGT-M) for Autosomal Dominant Polycystic Kidney Disease Following Kidney Transplant: A Case Report Wael Saad Elbanna, Osama Azmy, Manal Ahmed Elhinnawi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5438002/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease characterized by the development of cysts in the kidney. It is caused mainly by mutations in the PKD1 or PKD2 genes. Therefore, preimplantation genetic testing for monogenic kidney disease (PGT-M) is a promising strategy for preventing the transmission of the disease to the offspring. Case Presentation: Here, we present a case of ADPKD who underwent combined PGT-M and PGT-aneuploidy (PGT-A) and conceived a healthy fetus via intracytoplasmic sperm injection (ICSI). Ultimately, a healthy girl was born. Conclusion: PGT-M offers a way for ADPKD couples to have a successful pregnancy and reduce the risk of passing on the disease. Genetic counseling and a team approach are essential for the effective use of PGT-M in these cases. Autosomal Dominant Polycystic Kidney Disease Preimplantation Genetic Testing Reproductive Counselling Intracytoplasmic Sperm Injection Background Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease, affecting about 1:1000 to 1:2500 patients [ 1 ]. The disease is heterogeneous and is caused mainly by mutations in PKD1 (located on chromosome 16) or PKD2 genes (located on chromosome 4). More than 1500 mutations have been detected in the PKD1 and PKD2 genes among patients with ADPKD. Among them, mutations in the PKD1 gene are responsible for approximately 78–85% of the cases and cause more severe nephropathy than those in the PKD2 gene [ 1 – 3 ]. Moreover, about 50% of the offspring of couples with ADPKD have the chance of inheriting the disease [ 4 ]. ADPKD is clinically characterized by the unilateral or bilateral development of cysts in the kidney. The number of these cysts increases over time, resulting in nephromegaly and chronic renal failure. The extra-renal manifestations of ADPKD include cysts in the liver, seminal tract, pancreas, and intracranial aneurysms. Additionally, the disease is associated with infertility or subfertility in men due to the development of cysts in the seminal tract [ 1 – 3 , 5 ]. Notably, a significant proportion of patients with kidney disease often have a family history of the disease and may pass it to their future offspring. Therefore, early genetic testing is crucial for early identification and family risk counseling on the prognosis of the condition and treatment options [ 6 ]. However, a lack of family history of ADPKD was previously reported among 10–15% of the cases, mostly due to de novo mutations, mild phenotypes resulting from PKD2 mutations and non-truncating PKD1 mutations, or mosaicism [ 7 ]. Recently, Snoek et al. emphasized the heightened utilization of preimplantation genetic testing for monogenic kidney disease (PGT-M) in the Netherlands since 2009, underscoring its benefits for the offspring of couples with ADPKD [ 8 ]. PGT-M is performed as part of in-vitro fertilization (IVF) and is considered a promising reproductive choice for subjects carrying disease-causing genetic variants. It allows the identification and implementation of embryos that do not carry disease-causing genetic variants, leading to a significant reduction in disease transfer by > 95% [ 9 ]. Moreover, chromosomal abnormalities, especially aneuploidy, are well-established causes of implantation failure in IVF and early pregnancy loss. Therefore, preimplantation genetic testing for aneuploidy (PGT-A) is an effective strategy to reduce the number of transferred embryos during IVF procedures and increase the live birth rate per transfer [ 10 ]. Here, we present a case of successful combined PGT-M and PGT-A in preventing the transmission of ADPKD from a woman diagnosed with the disease, underwent kidney transplant, and conceived a fetus via intracytoplasmic sperm injection (ICSI). Case presentation This is a case of a 28-year-old woman diagnosed with polycystic kidney disease (PKD) who experienced pre-eclampsia during her previous pregnancy in 2016. She gave birth to a male fetus via cesarean section (CS), who was also diagnosed with PKD and died a year later due to a complication of the disease. After genetic counseling, a mutation in the PKD2 ((c.278 284 delinsAGGAGGAGGITAICCTCCTCCICCCCGC) (P. Glv93 lu95delinsGluGluGluValleLeuLeuleuProAla)) gene was detected. The patient had a negative family history, so the mutation in the PKD2 gene was considered de novo, and the variant was classified as a heterozygous variant of unknown significance (Supplementary File 1 and 2). In 2019, the kidney function of the patient deteriorated, and she underwent a kidney transplant followed by immunosuppression. Three years later, the patient had an IUD removed and experienced 1.5 years of secondary infertility before seeking pregnancy. Based on the previous obstetric history of the patient, a combination of PGT-M and PGT-A was recommended to exclude embryos carrying PKD-causing genetic variants. In December 2022, the patient underwent an antagonist protocol following consultation with the nephrologist staff. A transvaginal ultrasound-guided oocyte retrieval was performed, resulting in the retrieval of 5 oocytes. Out of these, four were injected for ICSI, and four embryos were then biopsied for PGT-M and PGT-A analysis (Supplementary File 3). The test results indicated one healthy female embryo and three affected embryos. The patient then began the hormone replacement therapy protocol for frozen embryo transfer, and her endometrium was ready for blastocyst transfer on day 20 of her cycle. A positive pregnancy blood test was confirmed 14 days after the transfer, and a subsequent ultrasound revealed a single gestational sac, confirming pregnancy. The prenatal ultrasounds during the pregnancy showed normal fetal development. Also, the patient had normal kidney function and blood pressure. At 29 weeks gestation, the ultrasound revealed polyhydramnios with the deepest vertical pocket measuring 10 cm. At 33 weeks gestation, there was premature rupture of the membranes and infrequent uterine contractions. Then, an urgent lower segment CS was performed, and a single living female fetus weighing 2200 grams was delivered. The baby was admitted to the neonatal intensive care unit (NICU) due to respiratory distress and received supplemental oxygen therapy, initially through Continuous Positive Airway Pressure (CPAP) for one day, followed by nasal oxygen for another day. The baby was assessed by a specialized nephrologist, and the findings of her renal and general examinations were normal. So, she was discharged and followed up and showed normal developmental milestones. Appropriate written informed consent for publication and personal medical information of this case report was requested and obtained. Discussion and Conclusion ADPKD is a monogenic autosomal dominant genetic disease characterized by renal cysts, deterioration of renal function, and chronic renal failure. Using PGT-M is effective in early detection and prevention of genetic disease transmission from one generation to another [ 7 ]. This case report demonstrates the successful application of combined PGT-M and PGT-A for the selection of embryos of a woman with ADPKD who underwent ICSI and conceived a healthy fetus. Several reports in the literature emphasized the promising findings of PGT among patients with monogenic kidney disease. In a 25-year cohort study in the Netherlands by Snoek et al., 53% of the couples with monogenic kidney disease proceeded to PGT, the mothers were more affected than the fathers, and 38% of them had ADPKD. Among the 537 embryos for biopsy, 35% were genetically unaffected and suitable for transfer, and about two-thirds of the offspring of couples experienced one or more live births of unaffected fetuses, comparable to IVF outcomes [ 8 ]. In another 10-year cohort study in China, the cumulative ongoing pregnancy/live birth rate was 54.69% among couples with a risk of genetic kidney disease (mostly PKD (34.3%)). Among their cohort, 344 embryos, 20.6% were unaffected euploid embryos, and 150 (43.6%) were free of genetic kidney disease and suitable for transfer [ 11 ]. Furthermore, Berckmoes and his colleagues have conducted a study to examine the factors affecting the success rate of couples performing PGT for PKD. The live birth delivery rates for fresh and frozen embryo transfer were 37.7% and 39.4%, respectively. The observed and expected cumulative live birth rates were 57.8% and 77.4%, respectively. Moreover, the authors concluded that only maternal age is significantly associated with the live birth delivery rate, a well-established risk factor for pregnancy outcomes in general [ 12 ]. Pardo et al. have examined the impact of the combination of PGT-M and PGT-A on the number of aneuploid embryos and the number of cycles with transferable embryos in ADPKD patients. Among 289 embryos, 49.3% were transferable, and 94.0% of cycles had transferable embryos (94.0% of cycles with PGT-M vs. 69.9% with combined PGT). Like Berckmoes et al., the authors also suggested that maternal age is the determinant factor for aneuploidy, not male infertility [ 13 ]. The age of the case presented here is 28, associated with a higher euploid blastocyst rate, higher live birth rates, and successful implementation [ 14 ]. Importantly, genetic counseling for couples with ADPKD on PGT-M should include information about the success rate, the cost, the waiting time, the technical limitations, and maternal health risks related to the procedure [ 8 ]. Here, the patient had a previous history of pre-eclampsia during her previous pregnancy and suffered from polyhydramnios, premature rupture of membrane, and delivery during the current one. In a previous case-control study, women with ADPKD have shown a non-significantly higher risk of spontaneous abortion and premature delivery. However, the risk of pre-eclampsia, hypertension, proteinuria, renal dysfunction, edema, and urinary tract infection was significantly different between groups [ 15 ]. Therefore, close maternal monitoring for pregnant women with ADPKD is crucial. In summary, PGT-M provides a promising approach for couples with ADPKD to achieve a successful pregnancy and reduce the chance of transmitting the disease to their children. Genetic counseling and a multidisciplinary team approach are crucial for the successful implementation of PGT-M in such cases. Further analysis of a larger cohort of ADPKD patients undergoing PGT-M is required to examine its impact on clinical practice and maternal and fetal outcomes. Abbreviations ADPKD Autosomal dominant polycystic kidney disease CPAP Continuous Positive Airway Pressure CS Cesarean section ICSI Intracytoplasmic sperm injection IVF In-vitro fertilization NICU Neonatal intensive care unit PGT Preimplantation genetic testing PGT-A Preimplantation genetic testing for aneuploidy PGT-M Preimplantation genetic testing for monogenic kidney disease PKD Polycystic kidney disease Declarations Ethics approval and consent to participate Written informed consent was obtained from the participant to be included in the study. Consent for publication Not applicable. Availability of Data and Material The data used during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no conflicts of interest. Funding We declare that this research received no external funding from any concerned constituent or pharmaceutical body. All work was conducted independently. Authors’ Contributions: WSE: Conceptualization, Methodology, Investigation, Data Curation,Validation, Resources, Writing—Original Draft, Writing—Review and Editing, Acquisition, Supervision. OA: Methodology, Acquisition, Writing— Review and Editing. MAE : Investigation, Data Curation, Writing—Review and Editing. All authors have read and agreed to the published version of the manuscript. Acknowledgment The authors would like to express their sincere gratitude to Dr. Omnia Mokbel, Research Unit Manager at El-Banna Group, for her valuable insights and thorough review throughout the research process. References Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet (London England). 2019;393:919–35. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321–37. Boucher C, Stanford R. Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). Eur J Hum Genet. 2004;12:347–54. Murphy EL, Droher ML, DiMaio MS, Dahl NK. Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease. Am J Kidney Dis. 2018;72:866–72. Vora N, Perrone R, Bianchi DW. Reproductive issues for adults with autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2008;51:307–18. Verma M. Genetic Testing Is Beneficial to the Entire Family. Clin J Am Soc Nephrol. 2020;15:1224. Chebib FT, Torres VE. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis. 2016;67:792. Snoek R, Stokman MF, Lichtenbelt KD, van Tilborg TC, Simcox CE, Paulussen ADC, et al. Preimplantation genetic testing for monogenic kidney disease. Clin J Am Soc Nephrol. 2020;15:1279–86. Kokkali G, Coticchio G, Bronet F, Celebi C, Cimadomo D, Goossens V et al. ESHRE PGT Consortium and SIG Embryology good practice recommendations for polar body and embryo biopsy for PGT. Hum Reprod open. 2020;2020. Murphy LA, Seidler EA, Vaughan DA, Resetkova N, Penzias AS, Toth TL, et al. To test or not to test? A framework for counselling patients on preimplantation genetic testing for aneuploidy (PGT-A). Hum Reprod. 2019;34:268–75. Xiao M, Shi H, Rao J, Xi Y, Zhang S, Wu J et al. Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis. Front Med. 2022;9. Berckmoes V, Verdyck P, De Becker P, De Vos A, Verheyen G, Van der Niepen P, et al. Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease. Hum Reprod. 2019;34:949–58. Pardo PM, Martínez-conejero JA, Martín J, Simón C, Cervero A. Combined Preimplantation Genetic Testing for Autosomal Dominant Polycystic Kidney Disease: Consequences for Embryos Available for Transfer. Genes 2020, Vol 11, Page 692. 2020;11:692. Taylor TH, Patrick JL, Gitlin SA, Crain JL, Wilson JM, Griffin DK. Blastocyst euploidy and implantation rates in a young (< 35 years) and old (≥ 35 years) presumed fertile and infertile patient population. Fertil Steril. 2014;102:1318–23. Wu M, Wang D, Zand L, Harris PC, White WM, Garovic VD, et al. Pregnancy Outcomes in Autosomal Dominant Polycystic Kidney Disease: a Case-Control Study. J Matern Fetal Neonatal Med. 2016;29:807. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFile1.ClinicalExomeSequencingResults.pdf SupplementaryFile2.VariantInterpretation.pdf SupplementaryFile3.PGTMResults.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5438002","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":381228770,"identity":"3a6cd732-e22a-4519-b54c-7784ff470a1b","order_by":0,"name":"Wael Saad Elbanna","email":"data:image/png;base64,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","orcid":"","institution":"Consultant at Hayat Women Care Center","correspondingAuthor":true,"prefix":"","firstName":"Wael","middleName":"Saad","lastName":"Elbanna","suffix":""},{"id":381228774,"identity":"c1b195ee-aa8a-479e-ba27-7a9de12ed91d","order_by":1,"name":"Osama Azmy","email":"","orcid":"","institution":"Egypt Centre for Research and Regenerative Medicine (ECRRM)","correspondingAuthor":false,"prefix":"","firstName":"Osama","middleName":"","lastName":"Azmy","suffix":""},{"id":381228775,"identity":"4fb74941-9f88-4b4f-8fdf-4d4930fc46dc","order_by":2,"name":"Manal Ahmed Elhinnawi","email":"","orcid":"","institution":"Hayat Women Care Center","correspondingAuthor":false,"prefix":"","firstName":"Manal","middleName":"Ahmed","lastName":"Elhinnawi","suffix":""}],"badges":[],"createdAt":"2024-11-12 09:08:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5438002/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5438002/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70904238,"identity":"ed58c8a1-0577-41af-8a73-825109c3984a","added_by":"auto","created_at":"2024-12-09 06:19:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":304503,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5438002/v1/476580bd-89cf-4f1f-b377-34b365330741.pdf"},{"id":70902304,"identity":"0a25795f-18ab-4c74-b72c-c1bfbedd9440","added_by":"auto","created_at":"2024-12-09 06:03:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":501562,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile1.ClinicalExomeSequencingResults.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5438002/v1/dc91258758e0fc95714c62ce.pdf"},{"id":70902305,"identity":"46e48f14-59be-4bfe-affb-e8e9d0b4d9da","added_by":"auto","created_at":"2024-12-09 06:03:24","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":783258,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile2.VariantInterpretation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5438002/v1/3e84a2e4c2cedcd5004145f4.pdf"},{"id":70902306,"identity":"9f53ee88-a109-4c71-aa5a-0629b255efb9","added_by":"auto","created_at":"2024-12-09 06:03:24","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1070656,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFile3.PGTMResults.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5438002/v1/d3742a9131729b8606c0062b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful Combined Preimplantation Genetic Testing for Aneuploidy (PGT-A) and for Monogenic Disorders (PGT-M) for Autosomal Dominant Polycystic Kidney Disease Following Kidney Transplant: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease, affecting about 1:1000 to 1:2500 patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disease is heterogeneous and is caused mainly by mutations in PKD1 (located on chromosome 16) or PKD2 genes (located on chromosome 4). More than 1500 mutations have been detected in the PKD1 and PKD2 genes among patients with ADPKD. Among them, mutations in the PKD1 gene are responsible for approximately 78\u0026ndash;85% of the cases and cause more severe nephropathy than those in the PKD2 gene [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moreover, about 50% of the offspring of couples with ADPKD have the chance of inheriting the disease [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eADPKD is clinically characterized by the unilateral or bilateral development of cysts in the kidney. The number of these cysts increases over time, resulting in nephromegaly and chronic renal failure. The extra-renal manifestations of ADPKD include cysts in the liver, seminal tract, pancreas, and intracranial aneurysms. Additionally, the disease is associated with infertility or subfertility in men due to the development of cysts in the seminal tract [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, a significant proportion of patients with kidney disease often have a family history of the disease and may pass it to their future offspring. Therefore, early genetic testing is crucial for early identification and family risk counseling on the prognosis of the condition and treatment options [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, a lack of family history of ADPKD was previously reported among 10\u0026ndash;15% of the cases, mostly due to de novo mutations, mild phenotypes resulting from PKD2 mutations and non-truncating PKD1 mutations, or mosaicism [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, Snoek et al. emphasized the heightened utilization of preimplantation genetic testing for monogenic kidney disease (PGT-M) in the Netherlands since 2009, underscoring its benefits for the offspring of couples with ADPKD [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePGT-M is performed as part of in-vitro fertilization (IVF) and is considered a promising reproductive choice for subjects carrying disease-causing genetic variants. It allows the identification and implementation of embryos that do not carry disease-causing genetic variants, leading to a significant reduction in disease transfer by \u0026gt;\u0026thinsp;95% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, chromosomal abnormalities, especially aneuploidy, are well-established causes of implantation failure in IVF and early pregnancy loss. Therefore, preimplantation genetic testing for aneuploidy (PGT-A) is an effective strategy to reduce the number of transferred embryos during IVF procedures and increase the live birth rate per transfer [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we present a case of successful combined PGT-M and PGT-A in preventing the transmission of ADPKD from a woman diagnosed with the disease, underwent kidney transplant, and conceived a fetus via intracytoplasmic sperm injection (ICSI).\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThis is a case of a 28-year-old woman diagnosed with polycystic kidney disease (PKD) who experienced pre-eclampsia during her previous pregnancy in 2016. She gave birth to a male fetus via cesarean section (CS), who was also diagnosed with PKD and died a year later due to a complication of the disease.\u003c/p\u003e \u003cp\u003eAfter genetic counseling, a mutation in the PKD2 ((c.278 284 delinsAGGAGGAGGITAICCTCCTCCICCCCGC) (P. Glv93 lu95delinsGluGluGluValleLeuLeuleuProAla)) gene was detected. The patient had a negative family history, so the mutation in the PKD2 gene was considered de novo, and the variant was classified as a heterozygous variant of unknown significance (Supplementary File 1 and 2).\u003c/p\u003e \u003cp\u003eIn 2019, the kidney function of the patient deteriorated, and she underwent a kidney transplant followed by immunosuppression. Three years later, the patient had an IUD removed and experienced 1.5 years of secondary infertility before seeking pregnancy. Based on the previous obstetric history of the patient, a combination of PGT-M and PGT-A was recommended to exclude embryos carrying PKD-causing genetic variants. In December 2022, the patient underwent an antagonist protocol following consultation with the nephrologist staff. A transvaginal ultrasound-guided oocyte retrieval was performed, resulting in the retrieval of 5 oocytes. Out of these, four were injected for ICSI, and four embryos were then biopsied for PGT-M and PGT-A analysis (Supplementary File 3). The test results indicated one healthy female embryo and three affected embryos. The patient then began the hormone replacement therapy protocol for frozen embryo transfer, and her endometrium was ready for blastocyst transfer on day 20 of her cycle. A positive pregnancy blood test was confirmed 14 days after the transfer, and a subsequent ultrasound revealed a single gestational sac, confirming pregnancy.\u003c/p\u003e \u003cp\u003eThe prenatal ultrasounds during the pregnancy showed normal fetal development. Also, the patient had normal kidney function and blood pressure. At 29 weeks gestation, the ultrasound revealed polyhydramnios with the deepest vertical pocket measuring 10 cm. At 33 weeks gestation, there was premature rupture of the membranes and infrequent uterine contractions. Then, an urgent lower segment CS was performed, and a single living female fetus weighing 2200 grams was delivered. The baby was admitted to the neonatal intensive care unit (NICU) due to respiratory distress and received supplemental oxygen therapy, initially through Continuous Positive Airway Pressure (CPAP) for one day, followed by nasal oxygen for another day. The baby was assessed by a specialized nephrologist, and the findings of her renal and general examinations were normal. So, she was discharged and followed up and showed normal developmental milestones. Appropriate written informed consent for publication and personal medical information of this case report was requested and obtained.\u003c/p\u003e "},{"header":"Discussion and Conclusion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cp\u003eADPKD is a monogenic autosomal dominant genetic disease characterized by renal cysts, deterioration of renal function, and chronic renal failure. Using PGT-M is effective in early detection and prevention of genetic disease transmission from one generation to another [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This case report demonstrates the successful application of combined PGT-M and PGT-A for the selection of embryos of a woman with ADPKD who underwent ICSI and conceived a healthy fetus.\u003c/p\u003e \u003cp\u003eSeveral reports in the literature emphasized the promising findings of PGT among patients with monogenic kidney disease. In a 25-year cohort study in the Netherlands by Snoek et al., 53% of the couples with monogenic kidney disease proceeded to PGT, the mothers were more affected than the fathers, and 38% of them had ADPKD. Among the 537 embryos for biopsy, 35% were genetically unaffected and suitable for transfer, and about two-thirds of the offspring of couples experienced one or more live births of unaffected fetuses, comparable to IVF outcomes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn another 10-year cohort study in China, the cumulative ongoing pregnancy/live birth rate was 54.69% among couples with a risk of genetic kidney disease (mostly PKD (34.3%)). Among their cohort, 344 embryos, 20.6% were unaffected euploid embryos, and 150 (43.6%) were free of genetic kidney disease and suitable for transfer [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, Berckmoes and his colleagues have conducted a study to examine the factors affecting the success rate of couples performing PGT for PKD. The live birth delivery rates for fresh and frozen embryo transfer were 37.7% and 39.4%, respectively. The observed and expected cumulative live birth rates were 57.8% and 77.4%, respectively. Moreover, the authors concluded that only maternal age is significantly associated with the live birth delivery rate, a well-established risk factor for pregnancy outcomes in general [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePardo et al. have examined the impact of the combination of PGT-M and PGT-A on the number of aneuploid embryos and the number of cycles with transferable embryos in ADPKD patients. Among 289 embryos, 49.3% were transferable, and 94.0% of cycles had transferable embryos (94.0% of cycles with PGT-M vs. 69.9% with combined PGT). Like Berckmoes et al., the authors also suggested that maternal age is the determinant factor for aneuploidy, not male infertility [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The age of the case presented here is 28, associated with a higher euploid blastocyst rate, higher live birth rates, and successful implementation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImportantly, genetic counseling for couples with ADPKD on PGT-M should include information about the success rate, the cost, the waiting time, the technical limitations, and maternal health risks related to the procedure [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, the patient had a previous history of pre-eclampsia during her previous pregnancy and suffered from polyhydramnios, premature rupture of membrane, and delivery during the current one. In a previous case-control study, women with ADPKD have shown a non-significantly higher risk of spontaneous abortion and premature delivery. However, the risk of pre-eclampsia, hypertension, proteinuria, renal dysfunction, edema, and urinary tract infection was significantly different between groups [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, close maternal monitoring for pregnant women with ADPKD is crucial.\u003c/p\u003e \u003cp\u003eIn summary, PGT-M provides a promising approach for couples with ADPKD to achieve a successful pregnancy and reduce the chance of transmitting the disease to their children. Genetic counseling and a multidisciplinary team approach are crucial for the successful implementation of PGT-M in such cases. Further analysis of a larger cohort of ADPKD patients undergoing PGT-M is required to examine its impact on clinical practice and maternal and fetal outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":" \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eADPKD\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eAutosomal dominant polycystic kidney disease\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCPAP\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eContinuous Positive Airway Pressure\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCS\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eCesarean section\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eICSI\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eIntracytoplasmic sperm injection\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIVF\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eIn-vitro fertilization\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eNICU\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003eNeonatal intensive care unit\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePGT\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003ePreimplantation genetic testing\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePGT-A\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003ePreimplantation genetic testing for aneuploidy\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePGT-M\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003ePreimplantation genetic testing for monogenic kidney disease\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePKD\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"Bold\" class=\"Bold\" name=\"Emphasis\"\u003ePolycystic kidney disease\u003c/span\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003cbr/\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the participant to be included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe declare that this research received no external funding from any concerned constituent or pharmaceutical body. All work was conducted independently.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWSE:\u003c/strong\u003e Conceptualization, Methodology, Investigation, Data Curation,Validation, Resources, Writing\u0026mdash;Original Draft, Writing\u0026mdash;Review and Editing, Acquisition, Supervision. \u003cstrong\u003eOA:\u003c/strong\u003e Methodology, Acquisition, Writing\u0026mdash; Review and Editing. \u003cstrong\u003eMAE\u003c/strong\u003e: Investigation, Data Curation, Writing\u0026mdash;Review and Editing. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their sincere gratitude to Dr. Omnia Mokbel, Research Unit Manager at El-Banna Group, for her valuable insights and thorough review throughout the research process.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet (London England). 2019;393:919\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoucher C, Stanford R. Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). Eur J Hum Genet. 2004;12:347\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurphy EL, Droher ML, DiMaio MS, Dahl NK. Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease. Am J Kidney Dis. 2018;72:866\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVora N, Perrone R, Bianchi DW. Reproductive issues for adults with autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2008;51:307\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerma M. Genetic Testing Is Beneficial to the Entire Family. Clin J Am Soc Nephrol. 2020;15:1224.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChebib FT, Torres VE. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis. 2016;67:792.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSnoek R, Stokman MF, Lichtenbelt KD, van Tilborg TC, Simcox CE, Paulussen ADC, et al. Preimplantation genetic testing for monogenic kidney disease. Clin J Am Soc Nephrol. 2020;15:1279\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKokkali G, Coticchio G, Bronet F, Celebi C, Cimadomo D, Goossens V et al. ESHRE PGT Consortium and SIG Embryology good practice recommendations for polar body and embryo biopsy for PGT. Hum Reprod open. 2020;2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurphy LA, Seidler EA, Vaughan DA, Resetkova N, Penzias AS, Toth TL, et al. To test or not to test? A framework for counselling patients on preimplantation genetic testing for aneuploidy (PGT-A). Hum Reprod. 2019;34:268\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao M, Shi H, Rao J, Xi Y, Zhang S, Wu J et al. Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis. Front Med. 2022;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerckmoes V, Verdyck P, De Becker P, De Vos A, Verheyen G, Van der Niepen P, et al. Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease. Hum Reprod. 2019;34:949\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePardo PM, Mart\u0026iacute;nez-conejero JA, Mart\u0026iacute;n J, Sim\u0026oacute;n C, Cervero A. Combined Preimplantation Genetic Testing for Autosomal Dominant Polycystic Kidney Disease: Consequences for Embryos Available for Transfer. Genes 2020, Vol 11, Page 692. 2020;11:692.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaylor TH, Patrick JL, Gitlin SA, Crain JL, Wilson JM, Griffin DK. Blastocyst euploidy and implantation rates in a young (\u0026lt;\u0026thinsp;35 years) and old (\u0026ge;\u0026thinsp;35 years) presumed fertile and infertile patient population. Fertil Steril. 2014;102:1318\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu M, Wang D, Zand L, Harris PC, White WM, Garovic VD, et al. Pregnancy Outcomes in Autosomal Dominant Polycystic Kidney Disease: a Case-Control Study. J Matern Fetal Neonatal Med. 2016;29:807.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Autosomal Dominant Polycystic Kidney Disease, Preimplantation Genetic Testing, Reproductive Counselling, Intracytoplasmic Sperm Injection","lastPublishedDoi":"10.21203/rs.3.rs-5438002/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5438002/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eAutosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease characterized by the development of cysts in the kidney. It is caused mainly by mutations in the PKD1 or PKD2 genes. Therefore, preimplantation genetic testing for monogenic kidney disease (PGT-M) is a promising strategy for preventing the transmission of the disease to the offspring.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eHere, we present a case of ADPKD who underwent combined PGT-M and PGT-aneuploidy (PGT-A) and conceived a healthy fetus via intracytoplasmic sperm injection (ICSI). Ultimately, a healthy girl was born.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003ePGT-M offers a way for ADPKD couples to have a successful pregnancy and reduce the risk of passing on the disease. Genetic counseling and a team approach are essential for the effective use of PGT-M in these cases.\u003c/p\u003e","manuscriptTitle":"Successful Combined Preimplantation Genetic Testing for Aneuploidy (PGT-A) and for Monogenic Disorders (PGT-M) for Autosomal Dominant Polycystic Kidney Disease Following Kidney Transplant: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 06:03:19","doi":"10.21203/rs.3.rs-5438002/v1","editorialEvents":[{"type":"communityComments","content":2}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6218f48-2128-4387-8c2e-d7d2aab931e5","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T06:03:21+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-09 06:03:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5438002","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5438002","identity":"rs-5438002","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}