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Preimplantation Genetic Testing (PGT) for non-traditional indications
RBMO VOLUME 38 ISSUE S1 2019
and mechanisms leading to early meiotic and mitotic errors as well as on the origin of mixoploid and chimaeric embryos. doi: 10.1016/j.rbmo.2019.03.005
PREIMPLANTATION GENETIC TESTING (PGT) FOR NONTRADITIONAL INDICATIONS
Svetlana Rechitsky, PhD, Anver Kuliev, MD, PhD Reproductive Genetic Innovations, LLC, 2910 MacArthur Boulevard, Northbrook, IL 60062, USA
Since the introduction of PGT, the indications for PGD are gradually expanding. Initially performed mainly for childhood-onset genetic conditions with clearly defined penetrance, severity and disease phenotypes, PGT is now applied to common late onset conditions determined by genetic predisposition, which may be realized with age or not realized in a lifetime. We present here the experience of PGT for these borderline indications in our series of over 17,000 PGT cases, which includes 5,780 PGT-M Of the521 conditions tested, the borderline indications included 71 cycles for cardiac conditions, 461 cycles for HLA matching and 702 cycles for cancer predisposition. Combined, these 1,163 cycles represent 20.1% of the overall cases. The most common cardiac genetic condition was Dilated Cardiomyopathy (DCM), 5causatives genes (over 30 different mutations), as well as Hypertrophic Cardiomyopathy (HCM) with 6 causative genes (over 16 different mutations). These cycles resulted in birth of 32 cardiac disease predisposition free children. The largest group for non-traditional indications was PGT-M for 23 cancer predisposition syndromes (642 cases overall), including BRCA1 and BRCA2, accounting for more than a third of the cases (32.7%;
210/642). These cycles resulted in birth of 271children free of cancer predisposition genes, which is the world's largest series. The number of cases for cancer predisposition syndromes has increased steadily since 1999, after we performed the world's fist PGT. The other group of PGT for non-traditional indications is PGT for HLA matching, which was requested either in combination with PGT-M (73.5% (339/461), or exclusively for HLA typing (26.5% (122/461), with or without PGT-A. Referrals for PGT are becoming increasingly complex as the improving testing technologies identify a wide genetic heterogeneity, variable severity and penetrance of adult onset conditions, for which the application of PGT may present importance ethical problems. However, our experience shows the increasing referral for PGT of such conditions, which was extremely accurate and efficient, allowing couples at risk to produce the offspring free of genes predisposing to common conditions of later life. doi: 10.1016/j.rbmo.2019.03.006
PGT FOR STRUCTURAL REARRANGEMENTS (PGT-SR)
Tomas Escudero Background: Patients with structural chromosome rearrangements encounter a variety of reproductive obstacles as a result of the high frequency of unbalanced gametes in these individuals, including low pregnancy rates, increase in spontaneous abortion (SAB) rate and an increased risk for unbalanced, genetically abnormal offspring1. The most common structural chromosome abnormality is the reciprocal translocation, seen in about 0.16% of the general population. A reciprocal translocation is the exchange of genetic material between two chromosomes; it is estimated
e3
that approximately 70% of embryos generated by a parent with a reciprocal translocation are abnormal. The next two most common structural chromosome abnormalities are Robertsonian translocations (0.1% of the general population) and inversions (0.02% of the general population). Other cases of structural chromosome abnormalities are less common, more complex, and supposedly precipitate the chances to have a successful outcome. Due to the scarcity of these cases these structural abnormalities have been poorly studied. For this study we include the chromosomal structural abnormalities classified as insertions and complex chromosome rearrangements (CCRs). Insertions are the relocation of a region of a chromosome to another location of the genome (whether the same chromosome or other chromosome), and CCRs are structural chromosome abnormalities involving three or more chromosomes. This study aims to determine the proportion of unbalanced embryos and reproductive risk to patients carrying insertions or CCR. Materials and methods: This study collects data from insertion and CCR cases analyzed by PGD techniques available at the time the case was processed. These techniques are fluorescence in situ hybridization (FISH), array comparative genome hybridization (aCGH), and next generation sequencing (NGS). CCR cases were classified further depending of the type of abnormalities of which the CCR is compounded (Table 1). 32 patients were included in this studies, from which 58 cycles were performed, and 517 embryos were analyzed
and mechanisms leading to early meiotic and mitotic errors as well as on the origin of mixoploid and chimaeric embryos. doi: 10.1016/j.rbmo.2019.03.005
PREIMPLANTATION GENETIC TESTING (PGT) FOR NONTRADITIONAL INDICATIONS
Svetlana Rechitsky, PhD, Anver Kuliev, MD, PhD Reproductive Genetic Innovations, LLC, 2910 MacArthur Boulevard, Northbrook, IL 60062, USA
Since the introduction of PGT, the indications for PGD are gradually expanding. Initially performed mainly for childhood-onset genetic conditions with clearly defined penetrance, severity and disease phenotypes, PGT is now applied to common late onset conditions determined by genetic predisposition, which may be realized with age or not realized in a lifetime. We present here the experience of PGT for these borderline indications in our series of over 17,000 PGT cases, which includes 5,780 PGT-M Of the521 conditions tested, the borderline indications included 71 cycles for cardiac conditions, 461 cycles for HLA matching and 702 cycles for cancer predisposition. Combined, these 1,163 cycles represent 20.1% of the overall cases. The most common cardiac genetic condition was Dilated Cardiomyopathy (DCM), 5causatives genes (over 30 different mutations), as well as Hypertrophic Cardiomyopathy (HCM) with 6 causative genes (over 16 different mutations). These cycles resulted in birth of 32 cardiac disease predisposition free children. The largest group for non-traditional indications was PGT-M for 23 cancer predisposition syndromes (642 cases overall), including BRCA1 and BRCA2, accounting for more than a third of the cases (32.7%;
210/642). These cycles resulted in birth of 271children free of cancer predisposition genes, which is the world's largest series. The number of cases for cancer predisposition syndromes has increased steadily since 1999, after we performed the world's fist PGT. The other group of PGT for non-traditional indications is PGT for HLA matching, which was requested either in combination with PGT-M (73.5% (339/461), or exclusively for HLA typing (26.5% (122/461), with or without PGT-A. Referrals for PGT are becoming increasingly complex as the improving testing technologies identify a wide genetic heterogeneity, variable severity and penetrance of adult onset conditions, for which the application of PGT may present importance ethical problems. However, our experience shows the increasing referral for PGT of such conditions, which was extremely accurate and efficient, allowing couples at risk to produce the offspring free of genes predisposing to common conditions of later life. doi: 10.1016/j.rbmo.2019.03.006
PGT FOR STRUCTURAL REARRANGEMENTS (PGT-SR)
Tomas Escudero Background: Patients with structural chromosome rearrangements encounter a variety of reproductive obstacles as a result of the high frequency of unbalanced gametes in these individuals, including low pregnancy rates, increase in spontaneous abortion (SAB) rate and an increased risk for unbalanced, genetically abnormal offspring1. The most common structural chromosome abnormality is the reciprocal translocation, seen in about 0.16% of the general population. A reciprocal translocation is the exchange of genetic material between two chromosomes; it is estimated
e3
that approximately 70% of embryos generated by a parent with a reciprocal translocation are abnormal. The next two most common structural chromosome abnormalities are Robertsonian translocations (0.1% of the general population) and inversions (0.02% of the general population). Other cases of structural chromosome abnormalities are less common, more complex, and supposedly precipitate the chances to have a successful outcome. Due to the scarcity of these cases these structural abnormalities have been poorly studied. For this study we include the chromosomal structural abnormalities classified as insertions and complex chromosome rearrangements (CCRs). Insertions are the relocation of a region of a chromosome to another location of the genome (whether the same chromosome or other chromosome), and CCRs are structural chromosome abnormalities involving three or more chromosomes. This study aims to determine the proportion of unbalanced embryos and reproductive risk to patients carrying insertions or CCR. Materials and methods: This study collects data from insertion and CCR cases analyzed by PGD techniques available at the time the case was processed. These techniques are fluorescence in situ hybridization (FISH), array comparative genome hybridization (aCGH), and next generation sequencing (NGS). CCR cases were classified further depending of the type of abnormalities of which the CCR is compounded (Table 1). 32 patients were included in this studies, from which 58 cycles were performed, and 517 embryos were analyzed