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International Journal of Molecular... Jun 2020Preimplantation genetic testing (PGT) is widely used today in in-vitro fertilization (IVF) centers over the world for selecting euploid embryos for transfer and to... (Review)
Review
BACKGROUND
Preimplantation genetic testing (PGT) is widely used today in in-vitro fertilization (IVF) centers over the world for selecting euploid embryos for transfer and to improve clinical outcomes in terms of embryo implantation, clinical pregnancy, and live birth rates.
METHODS
We report the current knowledge concerning these procedures and the results from different clinical indications in which PGT is commonly applied.
RESULTS
This paper illustrates different molecular techniques used for this purpose and the clinical significance of the different oocyte and embryo stage (polar bodies, cleavage embryo, and blastocyst) at which it is possible to perform sampling biopsies for PGT. Finally, genetic origin and clinical significance of embryo mosaicism are illustrated.
CONCLUSIONS
The preimplantation genetic testing is a valid technique to evaluated embryo euploidy and mosaicism before transfer.
Topics: Female; Fertilization in Vitro; Genetic Testing; Humans; Mosaicism; Ploidies; Pregnancy; Preimplantation Diagnosis
PubMed: 32575575
DOI: 10.3390/ijms21124381 -
F1000Research 2019Prenatal testing in recent years has been moving toward non-invasive methods to determine the fetal risk for genetic disorders without incurring the risk of miscarriage.... (Review)
Review
Prenatal testing in recent years has been moving toward non-invasive methods to determine the fetal risk for genetic disorders without incurring the risk of miscarriage. Rapid progress of modern high-throughput molecular technologies along with the discovery of cell-free fetal DNA in maternal plasma led to novel screening methods for fetal chromosomal aneuploidies. Such tests are referred to as non-invasive prenatal tests (NIPTs), non-invasive prenatal screening, or prenatal cell-free DNA screening. Owing to many advantages, the adoption of NIPT in routine clinical practice was very rapid and global. As an example, NIPT has recently become a standard screening procedure for all pregnant women in the Netherlands. On the other hand, invasive sampling procedures remain important, especially for their diagnostic value in the confirmation of NIPT-positive findings and the detection of Mendelian disorders. In this review, we focus on current trends in the field of NIPT and discuss their benefits, drawbacks, and consequences in regard to routine diagnostics.
Topics: Aneuploidy; Cell-Free Nucleic Acids; Female; Fetus; Genetic Testing; Humans; Pregnancy; Prenatal Diagnosis
PubMed: 31214330
DOI: 10.12688/f1000research.16837.1 -
Genes Mar 2021In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has... (Review)
Review
In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90-95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.
Topics: Chromosome Disorders; Female; Genetic Testing; Humans; Microarray Analysis; Pregnancy; Prenatal Diagnosis
PubMed: 33805390
DOI: 10.3390/genes12040501 -
Science Translational Medicine Jan 2011Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases...
Of 7028 disorders with suspected Mendelian inheritance, 1139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~10% of pediatric hospitalizations. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening to most severe disease genes has hitherto been impractical. Here, we report a preconception carrier screen for 448 severe recessive childhood diseases. Rather than costly, complete sequencing of the human genome, 7717 regions from 437 target genes were enriched by hybrid capture or microdroplet polymerase chain reaction, sequenced by next-generation sequencing (NGS) to a depth of up to 2.7 gigabases, and assessed with stringent bioinformatic filters. At a resultant 160x average target coverage, 93% of nucleotides had at least 20x coverage, and mutation detection/genotyping had ~95% sensitivity and ~100% specificity for substitution, insertion/deletion, splicing, and gross deletion mutations and single-nucleotide polymorphisms. In 104 unrelated DNA samples, the average genomic carrier burden for severe pediatric recessive mutations was 2.8 and ranged from 0 to 7. The distribution of mutations among sequenced samples appeared random. Twenty-seven percent of mutations cited in the literature were found to be common polymorphisms or misannotated, underscoring the need for better mutation databases as part of a comprehensive carrier testing strategy. Given the magnitude of carrier burden and the lower cost of testing compared to treating these conditions, carrier screening by NGS made available to the general population may be an economical way to reduce the incidence of and ameliorate suffering associated with severe recessive childhood disorders.
Topics: Base Sequence; Child; Databases, Genetic; Female; Genes, Recessive; Genetic Carrier Screening; Genetic Testing; Genome, Human; Heterozygote; Humans; Molecular Sequence Data; Mutation; Pregnancy; Prenatal Diagnosis; Sequence Alignment; Sequence Analysis, DNA
PubMed: 21228398
DOI: 10.1126/scitranslmed.3001756 -
Fertility and Sterility Mar 2014To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy. (Review)
Review
The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.
OBJECTIVE
To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy.
DESIGN
Retrospective.
SETTING
Academic.
PATIENT(S)
Trophectoderm biopsies.
INTERVENTION(S)
Comprehensive chromosomal screening performed on patients with blastocysts available for biopsy.
MAIN OUTCOME MEASURE(S)
Evaluation of the impact of maternal age on the prevalence of aneuploidy, the probability of having no euploid embryos within a cohort, the complexity of aneuploidy as gauged by the number of aneuploid chromosomes, and the trisomy/monosomy ratio.
RESULT(S)
Aneuploidy increased predictably after 26 years of age. A slightly increased prevalence was noted at younger ages, with >40% aneuploidy in women 23 years and under. The no euploid embryo rate was lowest (2% to 6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44. Among the biopsies with aneuploidy, 64% involved a single chromosome, 20% two chromosomes, and 16% three chromosomes, with the proportion of more complex aneuploidy increasing with age. Finally, the trisomy/monosomy ratio approximated 1 and increased minimally with age.
CONCLUSION(S)
The lowest risk for embryonic aneuploidy was between ages 26 and 30. Both younger and older age groups had higher rates of aneuploidy and an increased risk for more complex aneuploidies. The overall risk did not measurably change after age 43. Trisomies and monosomies are equally prevalent.
Topics: Adult; Aneuploidy; Biopsy; Blastocyst; Cohort Studies; Ectoderm; Female; Genetic Testing; Humans; Maternal Age; Middle Aged; Retrospective Studies; Young Adult
PubMed: 24355045
DOI: 10.1016/j.fertnstert.2013.11.004 -
Epidemiologic Reviews 2011Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist... (Review)
Review
Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element-information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research, but it also requires careful deliberation on the part of all concerned, including genomic researchers, clinicians, public health officials, health care payers, and especially those who will be the recipients of this novel screening approach.
Topics: Diagnostic Errors; Down Syndrome; Female; Genetic Carrier Screening; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant, Newborn; Mass Screening; Pregnancy; Prenatal Diagnosis; Primary Health Care
PubMed: 21709145
DOI: 10.1093/epirev/mxr008 -
Clinical Genetics Nov 2021Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of...
Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients-342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased.
Topics: Adult; Alleles; Amino Acid Substitution; Biomarkers; Child; Exons; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Hyperlipoproteinemia Type II; Male; Mutation; Phenotype; Quality Improvement; ROC Curve; Receptors, LDL
PubMed: 34297352
DOI: 10.1111/cge.14036 -
JBRA Assisted Reproduction Oct 2020Approximately 50% of the causes of infertility are of genetic origin. The objective of this study was to analyze the role of genetics in human reproduction by reviewing... (Review)
Review
Approximately 50% of the causes of infertility are of genetic origin. The objective of this study was to analyze the role of genetics in human reproduction by reviewing the main genetic causes of infertility and the use of preimplantation genetic testing in Brazil. This literature review comprised articles in English and Portuguese published on databases PubMed, Scielo, and Bireme from 1990 to 2019. Randomized clinical trials and specialized guidelines were given preference whenever possible. Genetic cause can be traced back to up to 20% of the cases of severe azoospermia or oligozoospermia. Subjects with these conditions are good candidates for genetic screening. In women, genetic causes of infertility (fragile X syndrome, X-trisomy, and Turner's syndrome, some of which diagnosed with karyotyping) culminate with premature ovarian failure. Genetic screening helps advise couples of the risk of experiencing early reproductive capacity loss and of the chances of their offspring carrying genetic disorders. In addition to enhancing the prevention of serious diseases in the offspring of couples at increased risk of genetic diseases, preimplantation genetic screening improves the success rates of assisted reproduction procedures by allowing the selection of euploid embryos for transfer. The interface between genetics and human reproduction has gained significant relevance, but discussions are still needed on which procedures are clinically and ethically acceptable and how they should be regulated.
Topics: Female; Genetic Counseling; Genetic Testing; Humans; Infertility; Male; Pregnancy; Preimplantation Diagnosis; Reproductive Techniques, Assisted
PubMed: 32293822
DOI: 10.5935/1518-0557.20200007 -
Molecular Systems Biology Nov 2022Spatial structure in biology, spanning molecular, organellular, cellular, tissue, and organismal scales, is encoded through a combination of genetic and epigenetic... (Review)
Review
Spatial structure in biology, spanning molecular, organellular, cellular, tissue, and organismal scales, is encoded through a combination of genetic and epigenetic factors in individual cells. Microscopy remains the most direct approach to exploring the intricate spatial complexity defining biological systems and the structured dynamic responses of these systems to perturbations. Genetic screens with deep single-cell profiling via image features or gene expression programs have the capacity to show how biological systems work in detail by cataloging many cellular phenotypes with one experimental assay. Microscopy-based cellular profiling provides information complementary to next-generation sequencing (NGS) profiling and has only recently become compatible with large-scale genetic screens. Optical screening now offers the scale needed for systematic characterization and is poised for further scale-up. We discuss how these methodologies, together with emerging technologies for genetic perturbation and microscopy-based multiplexed molecular phenotyping, are powering new approaches to reveal genotype-phenotype relationships.
Topics: Genetic Testing; High-Throughput Nucleotide Sequencing; Microscopy
PubMed: 36366905
DOI: 10.15252/msb.202110768 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2021Neonatal genetic disease is currently screened mainly based on metabolite biochemical technology. The false positive rate of biochemical screening technology is...
Neonatal genetic disease is currently screened mainly based on metabolite biochemical technology. The false positive rate of biochemical screening technology is relatively high, and there are certain false negatives, and only few types of diseases can be screened. The genetic techniques have been gradually used for neonatal genetic disease screening in recent years. Gene detection technology includes quantitative PCR (qPCR) and high-throughput sequencing. High-throughput sequencing includes gene panel sequencing, whole-exome sequencing and whole-genome sequencing. At present, qPCR and gene panel sequencing are the main technologies to be used for newborn genetic disease screening. Genetic screening diseases range from single disease such as hearing loss, spinal muscular atrophy and severe combined immunodeficiency to multiple diseases. Besides standards and guidelines for the interpretation of sequence variants proposed by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in 2015, the interpretation of genetic screening results should also consider biochemical results and other results. The development of newborn genetic screening needs to follow ethical principles, including the ethics of newborn genetic screening as a public health project, the privacy ethics of newborns and their family members, and the ethics of bioinformatics. The development of newborn genetic screening will enable more patients with inherited diseases to receive early diagnosis and treatment and improve their prognosis, which is a milestone in the field of neonatal screening.
Topics: Genetic Techniques; Genetic Testing; Genomics; Humans; Infant, Newborn; Neonatal Screening; United States; Exome Sequencing
PubMed: 34704410
DOI: 10.3724/zdxbyxb-2021-0288