Limitations of preimplantation genetic diagnosis for mitochondrial DNA diseases.
Ontology highlight
ABSTRACT:
SUBMITTER: Mitalipov S
PROVIDER: S-EPMC4349563 | biostudies-literature | 2014 May
REPOSITORIES: biostudies-literature
Publications
Limitations of preimplantation genetic diagnosis for mitochondrial DNA diseases.
Mitalipov Shoukhrat S Amato Paula P Parry Samuel S Falk Marni J MJ
Cell reports 20140501 4
Similar Datasets
Project description:ObjectiveTo explore inheritance of the m.3697G > A mitochondrial DNA (mtDNA) mutation and the effectiveness of preimplantation genetic diagnosis (PGD) for the carrier.MethodsThe study encompassed a pedigree of m.3697G > A mtDNA mutation, including one asymptomatic patient who pursued for PGD treatment. Twelve cumulus oocyte complexes (COCs) were collected in the first PGD cycle and 11 COCs in the second cycle. The efficiency of cumulus cells, polar bodies, and trophectoderm (TE) in predicting the m.3697G > A heteroplasmy of embryos was analyzed.ResultsFrom 23 COCs, 20 oocytes were fertilized successfully. On day 5 and 6 post-fertilization, 15 blastocysts were biopsied. The m.3697G > A mutation load of TE biopsies ranged from 15.2 to 100%. In the first cycle, a blastocyst with mutation load of 31.7% and chromosomal mosaicism was transferred, but failed to yield a clinical pregnancy. In the second cycle, a euploid blastocyst with mutation load of 53.9% was transferred, which gave rise to a clinical pregnancy. However, the pregnancy was terminated due to fetal cleft lip and palate. The mutation loads of different tissues (47.7 ± 1.8%) from the induced fetus were comparable to that of the biopsied TE and amniotic fluid cell (49.7%). The mutation load of neither cumulus cells (R2 = 0.02, p = 0.58) nor polar bodies (R2 = 0.33, p = 0.13) correlated with TE mutation load which was regarded as a gold standard.ConclusionsThe m.3697G > A mutation showed a random pattern of inheritance. PGD could be used to reduce the risk of inheritance of a high mutation load. Cumulus cells are not a suitable predictor of blastocyst mutation load.
| S-EPMC8666394 | biostudies-literature
Project description:The aim of this study was to explore factors contribute to the success of PGD cycles for monogenic diseases.During a 3-year period (January 2009 to December 2012), 184 consecutive ICSI-PGD cycles for monogenic diseases reaching the ovum pick-up and fresh embryo-transfer stage performed at the Reproductive Medicine Center of The First Affiliated Hospital Of Sun Yat-sen University were evaluated.ICSI was performed on 2206 metaphase II oocytes, and normal fertilization and cleavage rates were 83.4% (1840/2206) and 96.2% (1770/1840), respectively. In the present study, 60.5% (181/299) of day 3 good-quality embryos developed into good-quality embryos on day 4 after biopsy. Collectively, 42.9% clinical pregnancy rate (79/184) and 28.5% implantation rate (111/389) were presented. In the adjusted linear regression model, the only two significant factors affecting the number of genetically unaffected embryos were the number of biopsied embryos (coefficient: 0.390, 95%CI 0.317-0.463, P = 0.000) and basal FSH level (coefficient: 0.198, 95%CI 0.031-0.365, P = 0.021). In the adjusted binary logistic regression model, the only two significant factors affecting pregnancy outcome were the number of genetically available transferable embryos after PGD (adjusted OR 1.345, 95% CI 1.148-1.575, P = 0.000) and number of oocyte retrieved (adjusted OR 0.934, 95% CI 0.877-0.994, P = 0.031).There should be at least four biopsied embryos to obtain at least one unaffected embryos in a PGD system for patients with single gene disorder and under the condition of basal FSH level smaller than 8.0mmol/L. Moreover, if only a low number (< 4) of biopsied embryos are available on day 3, the chance of unaffected embryos for transfer was small, with poor outcome.
| S-EPMC4589384 | biostudies-other
Project description:PurposePreimplantation genetic testing (PGT) has become a reliable tool for preventing the germline transmission of mitochondrial DNA (mtDNA) variants. However, procedures are not standardized across mtDNA variants. In this study, we aim to estimate symptomatic thresholds, risk, and chance of success for PGT for mtDNA pathogenic variant carriers.MethodsWe performed a systematic analysis of heteroplasmy data including 455 individuals from 187 familial pedigrees with the common m.3243A>G, m.8344A>G, or m.8993T>G pathogenic variants. We applied binary logistic regression for estimating symptomatic thresholds of heteroplasmy, simplified Sewell-Wright formula and Kimura equations for predicting the risk of disease transmission, and binomial distribution for predicting minimum oocyte numbers.ResultsWe estimated the symptomatic thresholds of m.8993T>G and m.8344A>G as 29.86% and 16.15%, respectively. We could not determine a threshold for m.3243A>G. We established models for mothers harboring common and rare mtDNA pathogenic variants to predict the risk of disease transmission and the number of oocytes required to produce an embryo with sufficiently low variant load. In addition, we provide a table allowing the prediction of transmission risk and the minimum required oocytes for PGT patients with different variant levels.ConclusionWe have established models that can determine the symptomatic thresholds of common mtDNA pathogenic variants. We also constructed universal models applicable to nearly all mtDNA pathogenic variants which can predict risk and minimum numbers for PGT patients. These models have advanced our understanding of mtDNA disease pathogenesis and will enable more effective prevention of disease transmission using PGT.
| S-EPMC10440331 | biostudies-literature
Project description: Not available
| S-EPMC1954798 | biostudies-literature
Project description:Preimplantation genetic diagnosis (PGD) is a powerful tool to tackle the transmission of monogenic inherited disorders in families carrying the diseases from generation to generation. It currently remains a challenging task, despite PGD having been developed over 25 years ago. The major difficulty is it does not have an easy and general formula for all mutations. Different gene locus needs individualized, customized design to make the diagnosis accurate enough to be applied on PGD, in which the quantity of DNA is scanty, whereas timely laboratory diagnosis is mandatory if fresh embryo transfer is desired occasionally. Indicators for outcome assessment of a successful PGD program include the successful diagnosis rate on blastomeres (Day 3 cleavage-stage embryo biopsy) or trophectoderm cells (Day 5/6 blastocyst biopsy), the implantation rate per embryo transferred, and the livebirth rate per oocyte retrieval cycle. Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by various types of pathological defects in the factor VIII gene (F8). The mutation spectrum of the F8 is complex, according to our previous report, including large segmental intra-gene inversions, large segmental deletions spanning a few exons, point mutations, and total deletion caused by chromosomal structural rearrangements. In this review, the molecular methodologies used to tackle different mutants of the F8 in the PGD of HA are to be explained, and the experiences of successful use of amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR) and linkage analysis for PGD of HA in our laboratory are also provided.
| S-EPMC5056473 | biostudies-literature
Project description:Preimplantation genetic diagnosis (PGD) testing is the practice of obtaining a cellular biopsy sample from a developing human oocyte or embryo, acquired via a cycle of in vitro fertilization (IVF); evaluating the genetic composition of this sample; and using this information to determine which embryos will be optimal for subsequent uterine transfer. PGD has become an increasingly useful adjunct to IVF procedures. The ability to provide couples who are known carriers of genetic abnormalities the opportunity to deliver healthy babies has opened a new frontier in reproductive medicine. The purpose of the PGD is enables us to choose which embryos will be implanted into the mother. In the present study 137 families who had undergone IVF at Habib Medical Centre, were enrolled for the PGD analysis. The couple visited the clinic for the sex selection, recurrent fetal loss and with the recurrent IVF failure. 802 embryos were tested by the biopsy method and 512 are found to be normal and 290 were abnormal embryos. In this study only 24% of the embryos were transferred and the remaining was not transferred because of the abnormalities or undesired sex of the embryos. The structural and numerical abnormalities were found to be 16.8%.
| S-EPMC3670120 | biostudies-literature
Project description:Preimplantation genetic diagnosis (PGD) ensures a disease-causing variant is not passed to the next generation, including for inherited heart diseases. PGD is known to cause significant emotional burden, but little is known about how parents experience PGD to select against inherited heart disease. We aim to understand how people with inherited heart disease, and their partners, experience and make decisions about PGD. Participants were recruited from a specialised inherited heart disease clinic. Qualitative semi-structured interviews were conducted with adult participants who had considered PGD. A semi-structured interview schedule explored overall experiences and reasons for undergoing PGD. Broad topics included experience of disease, reproductive history, psychosocial and financial considerations. Interviews were recorded, transcribed verbatim and thematically analysed using a framework method. Twenty participants were included (15 with inherited cardiomyopathy, 3 with inherited arrhythmia syndrome and 2 partners). In contemplating PGD, participants considered 3 main issues: past experience of disease e.g. sudden cardiac death, sport restrictions and clinical heterogeneity; intergenerational responsibilities; and practical considerations such as finances and maternal age. Among those who chose to undergo PGD (n = 7/18), past experience of a significant cardiac event, such as family history of sudden cardiac death, was important in the decision process. The decision to undergo PGD for inherited heart disease is complex and influenced by individual values and experience of disease. We highlight key areas where further discussion may assist in PGD decision processes.
| S-EPMC8821668 | biostudies-literature
Project description:Preimplantation genetic diagnosis (PGD) allows birth of unaffected children for couples at risk for a genetic disorder. We present the strategy and outcome of PGD for four lysosomal storage disorders (LSD): Tay-Sachs disease (TSD), Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (HS), and subsequent development of stem cell lines. For each disease, we developed a family-specific fluorescent multiplex single-cell PCR protocol that included the familial mutation and informative markers surrounding the mutation. Embryo biopsy and PGD analysis were performed on either oocytes (polar bodies one and two) or on single blastomeres from a six-cell embryo. We treated twenty families carrying mutations in these lysosomal storage disorders, including 3 couples requiring simultaneous analysis for two disorders (TSD/GD, TSD/balanced Robertsonian translocation 45XYder(21;14), and HS/oculocutaneus albinism). These analyses led to an overall pregnancy rate/embryo transfer of 38% and the birth of 20 unaffected children from 17 families. We have found that PGD for lysosomal disorders is a safe and effective method to prevent birth of affected children. In addition, by using mutant embryos for the derivation of stem cell lines, we have successfully established GD and HS hESC lines for use as valuable models in LSD research.
| S-EPMC3540816 | biostudies-other
Project description:BackgroundPreimplantation 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).MethodsWe 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.ResultsInheritance 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.ConclusionsOur results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.
| S-EPMC4445980 | biostudies-literature
Project description:PURPOSE: To report the usage of PGD for alpha-thalassaemia with the - -(SEA) genotype. METHOD: A PGD protocol using fluorescent gap PCR was performed for 51 cycles on 43 couples with the - -(SEA) genotype. Allele drop-out and amplification failure rates were retrospectively analyzed. RESULTS: A total of 472 embryos were biopsied. Amplification was achieved in 390 blastomeres, accounting for an amplification rate of 82.6%. In total, 120 wild-type, 94 heterozygotes and 140 homozygous mutant embryos were diagnosed. The successful diagnosis rate was 75.0%. The ADO rate in 49 blastomeres from six donated embryos was 16.4%. One hundred and fifty four embryos were transferred, resulting in 25 clinical pregnancies with an implantation rate of 24.0%. CONCLUSIONS: Single-round fluorescent gap PCR is a feasible and effective strategy in the PGD for alpha-thalassaemia with the - -(SEA) genotype.
| S-EPMC2758951 | biostudies-other