Reproductive Genetics Institute

Chicago, IL, United States

Reproductive Genetics Institute

Chicago, IL, United States

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Rechitsky S.,Reproductive Genetics Institute | Verlinsky O.,Reproductive Genetics Institute | Kuliev A.,Reproductive Genetics Institute
Reproductive BioMedicine Online | Year: 2013

Preimplantation genetic diagnosis (PGD) for inherited disorders is presently applied for more than 300 different conditions. The most frequent PGD indication is cystic fibrosis (CF), the largest series of which is reviewed here, totalling 404 PGD cycles. This involved testing for 52 different CFTR mutations with almost half of the cases (195/404 cycles) performed for ΔF508 mutation, one-quarter (103/404 cycles) for six other frequent mutations and only a few for the remaining 45 CFTR mutations. There were 44 PGD cycles performed for 25 CF-affected homozygous or double-heterozygous CF patients (18 male and seven female partners), which involved testing simultaneously for three mutations, resulting in birth of 13 healthy CF-free children and no misdiagnosis. PGD was also performed for six couples at a combined risk of producing offspring with CF and another genetic disorder. Concomitant testing for CFTR and other mutations resulted in birth of six healthy children, free of both CF and another genetic disorder in all but one cycle. A total of 96 PGD cycles for CF were performed with simultaneous aneuploidy testing, including microarray-based 24-chromosome analysis, as a comprehensive PGD for two or more conditions in the same biopsy material. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Rechitsky S.,Reproductive Genetics Institute | Pakhalchuk T.,Reproductive Genetics Institute | San Ramos G.,Reproductive Genetics Institute | Goodman A.,Reproductive Genetics Institute | And 2 more authors.
Fertility and Sterility | Year: 2015

Objective To study the feasibility, accuracy, and reproductive outcome of 24-chromosome aneuploidy testing (24-AT), combined with preimplantation genetic diagnosis (PGD) for single-gene disorders (SGDs) or human leukocyte antigen (HLA) typing in the same biopsy sample. Design Retrospective study. Setting Preimplantation genetic diagnosis center. Patient(s) A total of 238 PGD patients, average age 36.8 years, for whom 317 combined PGD cycles were performed, involving 105 different conditions, with or without HLA typing. Intervention(s) Whole-genome amplification product, obtained in 24-AT, was used for PGD and/or HLA typing in the same blastomere or blastocyst biopsy samples. Main Outcome Measure(s) Proportion of the embryos suitable for transfer detected in these blastomere or blastocyst samples, and the resulting pregnancy and spontaneous abortion rates. Result(s) Embryos suitable for transfer were detected in 42% blastocyst and 25.1% blastomere samples, with a total of 280 unaffected, HLA-matched euploid embryos detected for transfer in 212 cycles (1.3 embryos per transfer), resulting in 145 (68.4%) unaffected pregnancies and birth of 149 healthy, HLA-matched children. This outcome is significantly different from that of our 2,064 PGD cycle series without concomitant 24-AT, including improved pregnancy (68.4% vs. 45.4%) and 3-fold spontaneous abortion reduction (5.5% vs. 15%) rates. Conclusion(s) The introduced combined approach is a potential universal PGD test, which in addition to achieving extremely high diagnostic accuracy, significantly improves reproductive outcomes of PGD for SGDs and HLA typing in patients of advanced reproductive age. © 2015 American Society for Reproductive Medicine.


Kuliev A.,Reproductive Genetics Institute
Practical Preimplantation Genetic Diagnosis | Year: 2013

Although treatment remains the major goal in the control of genetic disease, this is not yet a reality for most inherited conditions. In the absence of radical treatment, preimplantation genetic diagnosis (PGD) offers the answer to the control of these inherited conditions by predicting reproductive outcome. PGD is now entering its third decade as an established procedure for genetic and assisted reproduction practices, with new and exciting developments changing the whole concept of prevention of congenital disorders. The availability of practical experience from tens of thousands of PGD cases makes it necessary to update the current information on its accuracy, reliability and safety. The Second Edition of this successful book updates the progress in prevention of genetic disorders to demonstrate the important place of PGD in primary preventive measures and its increasing role in providing the whole range of reproduction options to couples at risk. In addition, it provides an extensive review of the most recent developments within the field of PGD including, PGD for expanding indications such as de novo mutations, cancers, inherited cardiac diseases and combined PGD for single gene disorders, HLA typing and 24 chromosome testing in patients of advance reproductive age. This practical book is vital for all practitioners within the field of fertility, reproductive medicine and medical genetics. It will also be useful for those responsible for planning and organizing PGD services and provides a working manual for the establishment and performance of PGD in the framework of IVF and genetic practices. © Springer-Verlag London 2012.


Kuliev A.,Reproductive Genetics Institute | Pomerantseva E.,Reproductive Genetics Institute | Polling D.,Reproductive Genetics Institute | Verlinsky O.,Reproductive Genetics Institute | Rechitsky S.,Reproductive Genetics Institute
Reproductive BioMedicine Online | Year: 2012

Preimplantation genetic diagnosis (PGD) has been applied for more than 200 different inherited conditions, with expanding application to common disorders with genetic predisposition. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. This paper presents the first, as far as is known, cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A total of 18 PGD cycles were performed, resulting in transfer in 15 of them, which yielded nine unaffected pregnancies and the births of seven disease- or disease predisposition-free children. The data open the prospect of PGD for inherited cardiac diseases, allowing couples carrying cardiac disease predisposing genes to reproduce without much fear of having offspring with these genes, which are at risk for premature or sudden death. Preimplantation genetic diagnosis (PGD) is currently an established clinical procedure in assisted reproduction and genetic practices. Its application has been expanding beyond traditional indications of prenatal diagnosis and currently includes common disorders with genetic predisposition, such as inherited forms of cancer. This applies also to the diseases with no current prospect of treatment, which may manifest despite presymptomatic diagnosis and follow up, when PGD may provide the only relief for the at-risk couples to reproduce. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. We present here our first cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A total of 18 PGD cycles for these disorders was performed, resulting in transfer in 15 of them, which yielded nine unaffected pregnancies and birth of seven disease- or disease predisposition-free children. The data open the prospect of PGD for inherited cardiac diseases, allowing couples carrying cardiac disease predisposing genes to reproduce without much fear of having offspring with these genes at risk for premature or sudden death. © 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Kuliev A.,Reproductive Genetics Institute
Expert Review of Obstetrics and Gynecology | Year: 2011

Preimplantation genetic diagnosis (PGD) was introduced more than 20 years ago and represents an established clinical procedure in assisted reproduction and genetic practices. This is now a reality that couples at genetic risk have a practical option to reproduce with less fear of producing offspring with genetic disorders. PGD has presently been applied to more than 220 different genetic disorders, with an over 99% accuracy rate in leading PGD centers. Its application has been expanding beyond traditional indications and includes some conditions determined by de novo mutations, common disorders with genetic predisposition, and HLA typing - with or without testing for causative genes. Despite recent controversy regarding the usefulness of PGD for assisted reproduction, the current developments in aneuploidy testing by microarray technology may improve preimplantation aneuploidy testing for the preselection of embryos with higher developmental potential, which is still the major challenge in improving IVF. This also makes it possible to combine the testing for different indications in one comprehensive procedure involving aneuploidy testing for 24 chromosomes, together with PGD for translocations, single-gene disorders and preimplantation HLA typing. This article describes these expanding applications of PGD, which are gradually becoming an integral part of prenatal care and assisted reproduction. © 2011 Expert Reviews Ltd.


Kuliev A.,Reproductive Genetics Institute | Zlatopolsky Z.,Reproductive Genetics Institute | Kirillova I.,Reproductive Genetics Institute | Spivakova J.,Reproductive Genetics Institute | Cieslak Janzen J.,Reproductive Genetics Institute
Reproductive BioMedicine Online | Year: 2011

This study presents the world's largest series of over 20,000 oocytes tested for aneuploidies, involving chromosomes 13, 16, 18, 21 and 22, providing the data on the rates and types of aneuploidies and their origin. Almost every second oocyte (46.8%) is abnormal, with predominance of extra chromatid errors predicting predominance of trisomies (53%) over monosomies (26%) in the resulting embryos (2:1), which is opposite to monosomy predominance observed in embryo testing. Of the detected anomalies in oocytes, 40% are complex, so testing for a few most prevalent chromosome errors may allow detection of the majority of abnormal embryos. Chromosome 21 and 22 errors are more prevalent, while two different patterns of error origin were observed for different chromosomes: chromosome 16 and 22 errors originate predominantly from meiosis II, compared with chromosome 13, 18 and 21 errors originating from meiosis I. This provides the first evidence for the differences in the aneuploid embryo survival depending on the meiotic origin. Considering the problem of mosaicism, which is the major limitation of the cleavage-stage testing, the direct oocyte aneuploidy testing by polar body analysis may be of obvious practical value in improving accuracy and reliability of avoiding aneuploid embryos for transfer. As much as 95% of chromosomal disorders originate from maternal meiosis, so we present here the meiosis errors detected in aneuploidy testing of over 20,000 oocytes in practice of preimplantation diagnosis, including the rates and types of aneuploidies and their origin. Almost every second oocyte in IVF patients aged over 38 is abnormal, originating from meiosis I and meiosis II. One-third of oocytes have both meiosis I and meiosis II errors, with the potential of correction in almost half of them involving the same chromosome. Chromatid errors constitute the major source of aneuploidy, predicting predominance of trisomies over monosomies in the resulting embryos, which contrasts to monosomy predominance observed in embryo testing. Of the detected anomalies in oocytes, 40% are complex, so testing for a few most prevalent chromosome errors may detect the majority of abnormal embryos. The smaller chromosome 21 and 22 errors are more prevalent, while there are two different patterns of error origin for different chromosomes: chromosome 16 and 22 errors originate predominantly from meiosis II, compared with chromosomes 13, 18 and 21 errors originating from meiosis I. This provides the first evidence for the differences in the aneuploid embryo survival depending on the meiotic origin. The data show that direct oocyte testing by polar body analysis may be of obvious practical value in improving accuracy and reliability of avoiding the transfer of aneuploid embryos. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Brezina P.R.,Johns Hopkins University | Benner A.,LabCorp | Rechitsky S.,Reproductive Genetics Institute | Kuliev A.,Reproductive Genetics Institute | And 4 more authors.
Fertility and Sterility | Year: 2011

Objective: To describe a method of amplifying DNA from blastocyst trophectoderm cells (two or three cells) and simultaneously performing 23-chromosome single nucleotide polymorphism microarrays and single-gene preimplantation genetic diagnosis. Design: Case report. Setting: IVF clinic and preimplantation genetic diagnostic centers. Patient(s): A 36-year-old woman, gravida 2, para 1011, and her husband who both were carriers of GM1 gangliosidosis. The couple wished to proceed with microarray analysis for aneuploidy detection coupled with DNA sequencing for GM1 gangliosidosis. Intervention(s): An IVF cycle was performed. Ten blastocyst-stage embryos underwent trophectoderm biopsy. Twenty-three-chromosome microarray analysis for aneuploidy and specific DNA sequencing for GM 1 gangliosidosis mutations were performed. Main Outcome Measure(s): Viable pregnancy. Result(s): After testing, elective single embryo transfer was performed followed by an intrauterine pregnancy with documented fetal cardiac activity by ultrasound. Conclusion(s): Twenty-three-chromosome microarray analysis for aneuploidy detection and single-gene evaluation via specific DNA sequencing and linkage analysis are used for preimplantation diagnosis for single-gene disorders and aneuploidy. Because of the minimal amount of genetic material obtained from the day 3 to 5 embryos (up to 6 pg), these modalities have been used in isolation of each other. The use of preimplantation genetic diagnosis for aneuploidy coupled with testing for single-gene disorders via trophectoderm biopsy is a novel approach to maximize pregnancy outcomes. Although further investigation is warranted, preimplantation genetic diagnosis for aneuploidy and single-gene testing seem destined to be used increasingly to optimize ultimate pregnancy success. Copyright © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.


Tur-Kaspa I.,Institute for Human Reproduction IHR | Tur-Kaspa I.,Reproductive Genetics Institute | Tur-Kaspa I.,University of Chicago
Seminars in Reproductive Medicine | Year: 2012

Patients who undergo in vitro fertilization (IVF) because of preimplantation genetic diagnosis (PGD) require different clinical management than those who come in because of infertility alone. PGD adds a "fourth dimensiono" to the emotional aspect of a patients' assisted reproductive technology treatment. It significantly decreases the number of embryos available for transfer by 25 to 81%, and therefore ovarian stimulation for IVF with PGD should be tailored individually, taking into account patients' safety and estimated ovarian reserve. Recent studies showed that with increased number of oocytes retrieved, the higher the chance to have an embryo transfer and normal cryopreserved blastocysts. With adequate ovarian stimulation, there is no cutoff for the numbers of oocytes/embryos needed to start PGD with, especially for younger patients. Patient-friendly protocols, such as those based on gonadotropin-releasing hormone antagonist and vaginal progesterone support may be used. Elective single embryo transfer and blastocysts cryopreservation to avoid multiple pregnancies may be offered with PGD. The benefit of adding preimplantation genetic screening to IVF treatment is still controversial, and evidence-based data on 24-chromosome testing of polar bodies or trophectoderm is needed before it may be implemented into routine patient care. This review discusses the clinical management of IVF with PGD based on the best available data and my personal clinical experience as a reproductive specialist with >1000 IVF/intracytoplasmic sperm injection-PGD cycles. The information provided here will assist reproductive specialists, nurses, geneticists, genetic counselors, and embryologists to better counsel and treat couples who wish to conceive with a healthy child through IVF with PGD. It is time for PGD to be viewed as a modern modality of preventive medicine. As such, it should be incorporated into national health-care systems and be covered by medical insurance. Copyright © 2012 by Thieme Medical Publishers, Inc.


Kuliev A.,Reproductive Genetics Institute | Rechitsky S.,Reproductive Genetics Institute
Molecular Human Reproduction | Year: 2011

Introduced > 20 years ago, the use of polar bodies (PBs), involving sequential removal and genetic analysis of the first (PB1) and second (PB2) PB, provides the option for pre-embryonic diagnosis, when the objection to the embryo biopsy procedures makes preimplantation genetic diagnosis (PGD) non-applicable. PB-based approach has presently been utilized in PGD for genetic and chromosomal disorders, applied either separately, or together with embryo biopsy approaches, especially if there are two or more PGD indications. We present here the world's largest experience of 938 PGD cycles for single-gene disorders performed by PB testing for 146 different monogenic conditions, which resulted in the birth of 345 healthy children (eight pregnancies are still ongoing), providing strong evidence that PBbased PGD is a reliable and safe procedure, with an extremely high accuracy rate of over 99%. With application of microarray technology, PB-based approach will be utilized for increasing number of indications, involving simultaneous testing for 24 chromosomes and single-gene disorders. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Rechitsky S.,Reproductive Genetics Institute | Pomerantseva E.,Reproductive Genetics Institute | Pakhalchuk T.,Reproductive Genetics Institute | Pauling D.,Reproductive Genetics Institute | And 2 more authors.
Reproductive BioMedicine Online | Year: 2011

Standard preimplantation genetic diagnosis (PGD) cannot be applied for de-novo mutations (DNM), because neither origin nor relevant haplotypes are available for testing in single cells. PGD strategies were developed for 80 families with 38 genetic disorders, determined by 33 dominant, three recessive and two X-linked DNM. All three recessive mutations were of paternal origin, while of 93 dominant mutations, 40 were paternal, 46 maternal and seven detected in affected children. The development of specific PGD strategy for each couple involved DNA analysis of the parents and affected children prior to PGD, including a mutation verification, polymorphic marker evaluation, whole and single sperm testing to establish the normal and mutant haplotypes and PGD by polar body analysis and/or embryo biopsy. Overall, 151 PGD cycles were performed for 80 families, for which a specific PGD design has been established. The application of these protocols resulted in pre-selection and transfer of 219 (1.72 per cycle) DNM-free embryos in 127 (84.1%) PGD cycles, yielding 63 (49.6%) unaffected pregnancies and birth of 59 (46.5%) healthy children, confirmed to be free of DNM. The data show feasibility of PGD for DNM, which may routinely be performed with accuracy of over 99%, using the established PGD strategy. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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