Testing For Single Gene Disorders Research Articles

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

EP424 - Preimplantation genetic testing for single gene disorders with human leukocyte antigen matching and aneuploidy screening: in vitro fertilization cycle outcomes

eP424 - Preimplantation genetic testing for single gene disorders with human leukocyte antigen matching and aneuploidy screening: in vitro fertilization cycle outcomes

Concurrent pre-implantation genetic testing for single gene disorders and aneuploidy screening from a single trophectoderm (TE) biopsy using targeted next generation sequencing (NGS) without whole genome amplification (WGA)

Concurrent pre-implantation genetic testing for single gene disorders and aneuploidy screening from a single trophectoderm (TE) biopsy using targeted next generation sequencing (NGS) without whole genome amplification (WGA)

Preimplantation genetic diagnosis for carriers of thalassemia and chromosomal abnormality

To provide preimplantation genetic diagnosis(PGD) for two couples carrying thalassemia mutations and chromosomal abnormalities. Couple 1 were both carriers of β 41/42 thalassemia mutations, while the husband has carried a reciprocal translocation with a karyotype of 46,XY,inv(9)(p11;q13),t(11;22)(q25;q13). Couple 2 were both carriers of α (-SEA) thalassemia mutation. Their chromosome karyotypes were both normal, but had two spontaneous abortions. The couples had received 1 and 3 blastocysts respectively through in vitro fertilization(IVF) cycles. Following the biopsy, the cells underwent whole genome amplification, and the amplified DNA from each embryo was subjected to genetic testing and a 23-chromosome single nucleotide polymorphism(SNP) microarray assay. The embryo of couple 1 was diagnosed as carrier of β 41/42 thalassemia with euploid chromosomes. The embryo was transferred and resulted in intrauterine pregnancy. Similarly, an embryo of couple 2 was verified as carrier of α (-SEA) thalassemia with euploid chromosomes. PGD for aneuploidy coupled with testing for single gene disorders via trophectoderm biopsy and whole genome amplification is feasible. The approach can attain diagnosis with minimal damage with sound clinical outcome.

First systematic experience of 24-chromosome aneuploidy testing in PGD for HLA and single gene disorders

24 chromosome aneuploidy testing have been introduced for pre-selection of embryos with improved potential to result in clinical pregnancy. This has a unique potential to combine with PGD for monogenic disorders, as the testing can be done in the same biopsy material, avoiding the risk for trisomy in the pre-selected genetic disease free embryos. So the first experience of systematic PGD with concomitant testing for single gene disorders, HLA typing and 24 chromosome testing is presented, involving the application of this novel approach to 55 different genetic conditions.

Progress in prenatal genetic diagnosis: Using cell-free fetal DNA in maternal blood

Non-invasive prenatal testing (Nipt) using cell-free fetal DNA (cffDNA) is an exciting area of development in prenatal diagnosis. CffDNA is found in maternal plasma from 4–5 weeks' gestation, enabling fetal genetic testing from a maternal blood sample, and thus avoiding the miscarriage risk associated with current invasive tests. Nipt is already established in the UK for predicting the rhesus D (RHD) type of the fetus in sensitised RhD-women and fetal sex determination for women who are carriers of sex-linked conditions. applications of Nipt likely to be available in the near future include testing for single gene disorders and chromosomal abnormalities, such as Down's syndrome, as well as routine fetal RHD typing for all RhD negative women. Midwives will play a key role in providing information to women and ensuring new tests are implemented effectively into practice. this article will provide an overview of the current developments in Nipt and discuss some of the ethical and social implications.

Non-invasive prenatal testing for single gene disorders: exploring the ethics

Non-invasive prenatal testing for single gene disorders is now clearly on the horizon. This new technology offers obvious clinical benefits such as safe testing early in pregnancy. Before widespread implementation, it is important to consider the possible ethical implications. Four hypothetical scenarios are presented that highlight how ethical ideals of respect for autonomy, privacy and fairness may come into play when offering non-invasive prenatal testing for single gene disorders. The first scenario illustrates the moral case for using these tests for 'information only', identifying a potential conflict between larger numbers of women seeking the benefits of the test and the wider social impact of funding tests that do not offer immediate clinical benefit. The second scenario shows how the simplicity and safety of non-invasive prenatal testing could lead to more autonomous decision-making and, conversely, how this could also lead to increased pressure on women to take up testing. In the third scenario we show how, unless strong safeguards are put in place, offering non-invasive prenatal testing could be subject to routinisation with informed consent undermined and that woman who are newly diagnosed as carriers may be particularly vulnerable. The final scenario introduces the possibility of a conflict of the moral rights of a woman and her partner through testing for single gene disorders. This analysis informs our understanding of the potential impacts of non-invasive prenatal testing for single gene disorders on clinical practice and has implications for future policy and guidelines for prenatal care.

Genetic testing for single gene disorders.

Genetic testing for single gene disorders is becoming available in Sri Lanka. While it offers many benefits, there are concerns about psychological and social problems that can be a consequence of such tests. This article aims to review the potential benefits and disadvantages of genetic testing, and recommends mechanisms that would help minimise problems associated with the inappropriate use of genetic tests.

Single-gene testing combined with single nucleotide polymorphism microarray preimplantation genetic diagnosis for aneuploidy: a novel approach in optimizing pregnancy outcome

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. Case report. IVF clinic and preimplantation genetic diagnostic centers. A 36-year-old woman, gravida 2, para 1011, and her husband who both were carriers of GM(1) gangliosidosis. The couple wished to proceed with microarray analysis for aneuploidy detection coupled with DNA sequencing for GM(1) gangliosidosis. 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. Viable pregnancy. After testing, elective single embryo transfer was performed followed by an intrauterine pregnancy with documented fetal cardiac activity by ultrasound. 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.

Evaluation of genetic tests for susceptibility to common complex diseases: why, when and how?

Recent research into the human genome has generated a wealth of scientific knowledge and increased both public and professional interest in the concept of personalised medicine. Somewhat unexpectedly, in addition to increasing our understanding about the genetic basis for numerous diseases, these new discoveries have also spawned a burgeoning new industry of 'consumer genetic testing'. In this paper, we present the principles learnt though the evaluation of tests for single gene disorders and suggest a comparable framework for the evaluation of genetic tests for susceptibility to common complex diseases. Both physicians and the general public will need to be able to assess the claims made by providers of genetic testing services, and ultimately policy-makers will need to decide if and when such tests should be offered through state funded healthcare systems.

Defining purpose: a key step in genetic test evaluation

The introduction of new genetic tests, like other medical innovations, can be conceptualized as a three-step process. Tests are proposed for use based on research findings and clinical reasoning; an evaluation occurs; and judgments are made about clinical use and reimbursement (Fig. 1). The evaluation may be informal, as when a clinician determines whether a new test will be helpful in a particular patient encounter, or formal, as when a practice guideline panel utilizes a defined methodology to assess a test or a health care funder utilizes a set of criteria to determine test coverage. Although genetic tests are often described in terms of technology, a full evaluation requires that the test be considered as a clinical process in which the laboratory assay, or other testing procedure, is done to acquire information about a particular health condition, in a defined population, for a specific clinical purpose.1 Genetic tests have a wide range of health care applications. They are used to confirm the presence of a genetic condition, identify reproductive risks, and select preventive therapy. Testing occurs in newborn screening programs and in primary, specialty, and prenatal care, and may be initiated on the basis of clinical symptoms, family history, or population demographics. Genetic tests also utilize a range of technologies, and vary considerably in their predictive value. This diversity poses a challenge for the evaluation process. Several groups have considered methods for genetic test evaluation,2–5 and model programs for systematic evaluation have been established in the United States (Evaluation of Genomic Applications in Practice and Prevention6) and the UK (the UK Genetic Testing Network7). To date, however, the evaluation process has not fully addressed the clinical diversity of genetic tests. The Evaluation of Genomic Applications in Practice and Prevention project has focused on genetic tests related to common disorders and drug therapy, whereas the United Kingdom Genetic Testing Network has primarily addressed tests for single gene disorders. An effort by the Secretary’s Advisory Committee on Genetic Testing to categorize genetic tests into those requiring higher versus lower levels of scrutiny was not successful.8 To address the challenge of genetic test diversity, we propose an outcome-orientated taxonomy for defining test purpose. A focus on health outcomes allows the definition of a small and informative set of purposes for genetic testing, despite the range of technologies and clinical settings in which testing occurs. Defining test purpose in turn clarifies the benefits to be expected from the testing process, and provides guidance to clinicians and policy makers concerning the evidence needed to support test use. Defining test purpose, therefore, is an important first step in genetic test evaluation.

Detection of chromosome aberrations during prenatal genetic testing for single gene disorders

Detection of chromosome aberrations during prenatal genetic testing for single gene disorders

Detection of chromosome aberrations during prenatal genetic testing for single gene disorders

Detection of chromosome aberrations during prenatal genetic testing for single gene disorders

Searching for genes in diabetes and the metabolic syndrome

Evidence for a genetic basis for type 2 diabetes and the metabolic syndrome has been derived from studies of families, twins and populations with genetic admixture. Identification of genes associated with disease pathogenesis is now underway using techniques such as genome scanning by positional cloning and the candidate gene approach. Genome scanning in several different ethnic groups has identified chromosome regions harbouring type 2 diabetes susceptibility genes such as the novel gene, calpain 10 (CAPN10). The hepatic nuclear factor 4alpha (HNF4alpha) gene partly explains the linkage peak on chromosome 20, while the upstream transcription factor (USF1) is associated with familial combined hyperlipidaemia (FCHL) and maps close to the type 2 diabetes associated 1q peak. Peroxisome proliferator-activated receptor gamma (PPARgamma) was identified as a candidate gene based on its biology. A Pro12Ala variant of this gene has been associated with an increased risk of type 2 diabetes. Many genes accounting for monogenic forms of diabetes have been identified--such as maturity onset diabetes of the young (MODY); glucokinase (GCK) and HNF1alpha mutations being the most common causes of MODY. GCK variants result in 'mild' diabetes or impaired glucose tolerance (IGT) and relatively few cardiovascular complications, while HNF1alpha-associated MODY is more typical of type 2 diabetes, frequently being treated with sulphonylureas or insulin and resulting in microvascular complications. Testing for single gene disorders associated with type 2 diabetes and obesity may determine cause, prognosis and appropriate treatment; however, for the more common polygenic diseases this is not the case. In type 2 diabetes, molecular genetics has the potential to enhance understanding of disease pathogenesis, and help formulate preventative and treatment strategies.

Ethical issues in DNA testing.

Molecular tests for single gene disorders have become the "gold standard," surpassing in sensitivity and specificity other ancillary tests such as imaging or neurophysiologic tests. Although direct technical problems are rare for DNA tests, few outcomes studies have been reported that examine sensitivity, specificity, and usage of tests outside the setting of academic medical centers. Ethical problems of DNA testing are mainly discussed in a theoretical framework and few published studies or case reports deal with real-life situations. Among neurologists, ethical dilemmas and attempts at their resolution are communicated mainly on a verbal basis, and even then relatively little follow-up is available. The potential use of information obtained through DNA testing by other family members, employers, insurance companies, and governmental agencies deserves scientific investigation and societal discussion. A major educational effort is needed to inform patients, providers, and third parties that the presence of a particular allele in an individual is only one piece in a complex puzzle of environmental and genetic interactions that may ultimately result in disease.

Molecular Analysis and Chorionic Villus Sampling (CVS): Opportunities for Rapid Prenatal Diagnosis in the Military

Prior to recent advances in the field of molecular biology, prenatal diagnosis of hemoglobinopathies was accomplished by direct analysis of the gene product(s) in samples obtained by fetoscopy or, more recently, percutaneous umbilical blood sampling. The use of the polymerase chain reaction enables quicker diagnosis than with indirect or cumbersome Southern blot techniques. This case, reporting a couple at risk for fetal sickle cell disease, is a model for rapid prenatal diagnosis and demonstrates the capabilities which exist in the military health care referral system. Within 24 hours of a couple's presentation for consultation and accomplishment of chorionic villus sampling (CVS), preliminary results of both cytogenetic and sickle cell status of an at-risk fetus were determined. Final analysis was accomplished by 48 hours. The combination of early referral, early sampling by CVS, and application of advances in DNA laboratory technologies offers tremendous improvements for care heretofore unavailable as a complete "package" in the military. The implications and limitations for prenatal testing for single gene disorders within the military medical health care system will be discussed.