Implications of genetic testing and informed consent before and after genetic testing in individuals with cancer

Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of access to geneticists,medical oncologists and other treating physicians have begun ordering and interpreting genetic tests for individuals with cancer through the process of"mainstreaming".While this process has allowed for quicker access to genetic tests,the process of"mainstreaming"has also brought several challenges including the dissemination of variants of unknown significance results,ordering of appropriate tests,and accurate interpretation of genetic results with appropriate followup testing and interventions.In this editorial,we seek to explore the process of informed consent of individuals before obtaining genetic testing and offer potential solutions to optimize the informed consent process including categorization of results as well as a layered consent model.

Relationship Between Gene-Phenotype and Clinical Manifestations of Chromosomal Copy Number Variations Indicated by Non-Invasive Prenatal Testing

Objective:To analyze the clinical value of non-invasive prenatal testing(NIPT)in detecting chromosomal copy number variations(CNVs)and to explore the relationship between gene expression and clinical manifestations of chromosomal copy number variations.Methods:3551 naturally conceived singleton pregnant women who underwent NIPT were included in this study.The NIPT revealed abnormalities other than sex chromosome abnormalities and trisomy 13,18,and 21.Pregnant women with chromosome copy number variations underwent genetic counseling and prenatal ultrasound examination.Interventional prenatal diagnosis and chromosome microarray analysis(CMA)were performed.The clinical phenotypes and pregnancy outcomes of different prenatal diagnoses were analyzed.Additionally,a follow-up was conducted by telephone to track fetal development after birth,at six months,and one year post-birth.Results:A total of 53 cases among 3551 cases showed chromosomal copy number variation.Interventional prenatal diagnosis was performed in 36 cases:27 cases were negative and 8 were consistent with the NIPT test results.This indicates that NIPT’s positive predictive value(PPV)in CNVs is 22.22%.Conclusion:NIPT has certain clinical significance in screening chromosome copy number variations and is expected to become a routine screening for chromosomal microdeletions and microduplications.However,further interventional prenatal diagnosis is still needed to identify fetal CNVs.

Genetic testing in congenital heart disease:A clinical approach

Congenital heart disease(CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient followup. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel.

Predictive potential of IL-28B genetic testing for interferon based hepatitis C virus therapy in Pakistan: Current scenario and future perspective

In Pakistan which ranked second in terms of hepatitis C virus(HCV) infection, it is highly needed to have an established diagnostic test for antiviral therapy responseprediction. Interleukin 28B(IL-28B) genetic testing is widely used throughout the world for interferon based therapy prediction for HCV patients and is quite helpful not only for health care workers but also for the patients. There is a strong relationship between single nucleotide polymorphisms at or near the IL-28 B gene and the sustained virological response with pegylated interferon plus ribavirin treatment for chronic hepatitis C. Pakistan is a resource limited country, with very low per capita income and there is no proper social security(health insurance) system. The allocated health budget by the government is very low and is used on other health emergencies like polio virus and dengue virus infection. Therefore it is proposed that there should be a well established diagnostic test on the basis of IL-28 B which can predict the antiviral therapy response to strengthen health care set-up of Pakistan. This test once established will help in better management of HCV infected patients.

Non-invasive genetic analysis indicates low population connectivity in vulnerable Chinese gorals:concerns for segregated population management

Detailed information on the size and genetic structure of wildlife populations is critical for developing effective conservation strategies, especially for those species that have suffered population decline and fragmentation due to anthropogenic activities. In the present study, we used a non-invasive approach combining fecal pellet sampling with mitochondrial DNA and nuclear DNA microsatellite marker analysis to monitor and compare the population structure of the Chinese goral (Naemorhedus griseus) in Beijing and northeast Inner Mongolia in China. Of the 307 fecal samples confirmed to be from N. griseus, 15 individuals (nine females and six males) were found in the Beijing population and 61 individuals (37 females and 24 males) were found in the Inner Mongolian population. Among these 76 individuals, we identified eight haplotypes and 13 nucleotide polymorphic sites from mtDNA and 45 alleles from 10 microsatellite loci. Spatially structured genetic variation and a significant level of genetic differentiation were observed between the two populations. In both populations, the sex ratios were skewed toward females, indicating high reproductive potential, which is crucial for population recovery and conservation of this patchily distributed vulnerable species. We suggest that managing the two populations as evolutionarily significant units with diverse genetic backgrounds could be an effective solution for present population recovery, with the possible relocation of individuals among different groups to help ensure future goral species prosperity.

Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing

Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.

Genetic testing vs microforceps biopsy in pancreatic cysts:Systematic review and meta-analysis

BACKGROUND Carcinoembryonic antigen(CEA)and cytology in pancreatic cystic fluid are suboptimal for evaluation of pancreatic cystic neoplasms.Genetic testing and microforceps biopsy are promising tools for pre-operative diagnostic improvement but comparative performance of both methods is unknown.AIM To compare the accuracy of genetic testing and microforceps biopsy in pancreatic cysts referred for surgery.METHODS We performed a literature search in Medline,Scopus,and Web of Science for studies evaluating genetic testing of cystic fluid and microforceps biopsy of pancreatic cysts,with endoscopic ultrasound with fine-needle aspiration(EUSFNA)prior to surgery and surgical pathology as reference standard for diagnosis.We evaluated the diagnostic accuracy for:1-benign cysts;2-mucinous low-risk cysts;3-high-risk cysts,and the diagnostic yield and rate of correctly identified cysts with microforceps biopsy and molecular analysis.We also assessed publication bias,heterogeneity,and study quality.RESULTS Eight studies,including 1206 patients,of which 203(17%)referred for surgery who met the inclusion criteria were analyzed in the systematic review,and seven studies were included in the meta-analysis.Genetic testing and microforceps biopsies were identical for diagnosis of benign cysts.Molecular analysis was superior for diagnosis of both low and high-risk mucinous cysts,with sensitivities of 0.89(95%CI:0.79-0.95)and 0.57(95%CI:0.42-0.71),specificities of 0.88(95%CI:0.75-0.95)and 0.88(95%CI:0.80-0.93)and AUC of 0.9555 and 0.92,respectively.The diagnostic yield was higher in microforceps biopsies than in genetic analysis(0.73 vs 0.54,respectively)but the rates of correctly identified cysts were identical(0.73 with 95%CI:0.62-0.82 vs 0.71 with 95%CI:0.49-0.86,respectively).CONCLUSION Genetic testing and microforceps biopsies are useful second tests,with identical results in benign pancreatic cysts.Genetic analysis performs better for low-and high-risk cysts but has lower diagnostic yield.

Should multi-gene panel testing replace limited BRCA1/2 testing? A review of genetic testing for hereditary breast and ovarian cancers

Clinical testing of patients for hereditary breast and ovarian cancer syndromes began in the mid-1990s with the identification of the BRCA1 and BRCA2 genes.Since then,mutations in dozens of other genes have been correlated to increased breast,ovarian,and other cancer risk.The following decades of data collection and patient advocacy allowed for improvements in medical,legal,social,and ethical advances in genetic testing.Technological advances have made it possible to sequence multiple genes at once in a panel to give patients a more thorough evaluation of their personal cancer risk.Panel testing increases the detection of mutations that lead to increased risk of breast,ovarian,and other cancers and can better guide individualized screening measures compared to limited BRCA testing alone.At the same time,multi-gene panel testing is more time-and cost-efficient.While the clinical application of panel testing is in its infancy,many problems arise such as lack of guidelines for management of newly identified gene mutations,high rates of variants of uncertain significance,and limited ability to screen for some cancers.Through on-going concerted efforts of pooled data collection and analysis,it is likely that the benefits of multi-gene panel testing will outweigh the risks in the near future.

Clinicopathological analysis of early-stage breast cancer patients that meet indications for BRCA 1/2 genetic testing

Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in China.Methods:Based on the indication criteria for BRCA genetic testing specified in the National Comprehensive Cancer Network(NCCN)clinical practice guidelines in oncology,genetic/familial high-risk assessment:Breast and ovarian(Version 2.2019),a retrospective analysis was performed on patients with early-stage invasive breast cancer treated at Breast Disease Center,Peking University First Hospital between January 2008 and December 2016.Clinicopathological characteristics of all patients were analyzed,and prognoses were calculated using the KaplanMeier method and a Cox proportionate hazards model.Results:A total of 906 early-stage breast cancer patients who had indications for BRCA genetic testing and had complete clinicopathological data and follow-up information were included in the study group,accounting for34.7%of all breast cancer patients treated in Breast Disease Center,Peking University First Hospital during the study period.Compared with breast cancer patients without indications for BRCA genetic testing,the overall survival(OS)and disease-free survival(DFS)of patients with indications were not significantly different.In the study group,patients with premenopausal status,high T stage,lymph node positive,estrogen receptor(ER)negative,Ki-67>20%and presence of a vascular tumor thrombus had worse prognosis.There were more family histories of gastrointestinal cancer in patients with related indications than in patients without such indications.Conclusions:Single-center data showed that more than 30%of patients with early-stage breast cancer had indications for BRCA genetic testing.There was no prognostic difference in patients with or without indications for BRCA genetic testing.Premenopausal status,high T stage,lymph node positive,ER negative,Ki-67>20%,and presence of a vascular tumor thrombus were associated with poor prognosis.

Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing

The introduction of next-generation sequencing(NGS) technology in testing for hereditary cancer susceptibility allows testing of multiple cancer susceptibility genes simultaneously. While there are many potential benefits to utilizing this technology in the hereditary cancer clinic, including efficiency of time and cost, there are also important limitations that must be considered. The best panel for the given clinical situation should be selected to minimize the number of variants of unknown significance. The inclusion in panels of low penetrance or newly identified genes without specific actionability can be problematic for interpretation.Genetic counselors are an essential part of the hereditary cancer risk assessment team, helping the medical team select the most appropriate test and interpret the often complex results. Genetic counselors obtain an extended family history, counsel patients on the available tests and the potential implications of results for themselves and their family members(pre-test counseling), explain to patients the implications of the test results(post-test counseling), and assist in testing family members at risk.

Genetic testing in neurology exploiting next generation sequencing:state of art

Next generations sequencing (NGS) is definitely one of the most revolutionary technology of the last years in genetic and medical field (Kricka and Di Resta, 2013). It brought important changes in genetic testing of inherited human disorders, in particular in neurological Mendelian forms, such as inherited neuropathies, ataxias or monogenic form of epilepsy, where “diagnostic odyssey” is quite common.

Role of genetic testing in cardiomyopathies:Αprimer for cardiologists

Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies.As novel mutations have been identified,understanding when to consider genetic testing has emerged as an important consideration in the management of these cases.Specific genetic testing has a paramount importance in the risk stratification of family members,in the prognosis of probands at higher risk of a serious phenotype expression,and finally in the identification of new mutations,all of which are discussed in this review.The indications for each type of cardiomyopathy are described,along with the limitations of genetic testing.Finally,the importance of public sharing of variants in large data sets is emphasized.The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.

An Optimized Test Case Minimization Technique Using Genetic Algorithm for Regression Testing

Regression testing is a widely used approach to confirm the correct functionality of the software in incremental development.The use of test cases makes it easier to test the ripple effect of changed requirements.Rigorous testingmay help in meeting the quality criteria that is based on the conformance to the requirements as given by the intended stakeholders.However,a minimized and prioritized set of test cases may reduce the efforts and time required for testingwhile focusing on the timely delivery of the software application.In this research,a technique named Test Reduce has been presented to get a minimal set of test cases based on high priority to ensure that the web applicationmeets the required quality criteria.A new technique TestReduce is proposed with a blend of genetic algorithm to find an optimized and minimal set of test cases.The ultimate objective associated with this study is to provide a technique that may solve the minimization problem of regression test cases in the case of linked requirements.In this research,the 100-Dollar prioritization approach is used to define the priority of the new requirements.

Value-Based Test Case Prioritization for Regression Testing Using Genetic Algorithms

Test Case Prioritization(TCP)techniques perform better than other regression test optimization techniques including Test Suite Reduction(TSR)and Test Case Selection(TCS).Many TCP techniques are available,and their performance is usually measured through a metric Average Percentage of Fault Detection(APFD).This metric is value-neutral because it only works well when all test cases have the same cost,and all faults have the same severity.Using APFD for performance evaluation of test case orders where test cases cost or faults severity varies is prone to produce false results.Therefore,using the right metric for performance evaluation of TCP techniques is very important to get reliable and correct results.In this paper,two value-based TCP techniques have been introduced using Genetic Algorithm(GA)including Value-Cognizant Fault Detection-Based TCP(VCFDB-TCP)and Value-Cognizant Requirements Coverage-Based TCP(VCRCB-TCP).Two novel value-based performance evaluation metrics are also introduced for value-based TCP including Average Percentage of Fault Detection per value(APFDv)and Average Percentage of Requirements Coverage per value(APRCv).Two case studies are performed to validate proposed techniques and performance evaluation metrics.The proposed GA-based techniques outperformed the existing state-of-the-art TCP techniques including Original Order(OO),Reverse Order(REV-O),Random Order(RO),and Greedy algorithm.

Discrepancy between non-invasive prenatal testing result and fetal karyotype caused by rare confined placental mosaicism: A case report

BACKGROUND Confined placental mosaicism(CPM)is one of the major reasons for discrepancies between the results of non-invasive prenatal testing(NIPT)and fetal karyotype analysis.CASE SUMMARY We encountered a primiparous singleton pregnant woman with a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,who obtained a false-positive result on NIPT with a high risk for trisomy 21.Copy-number variation sequencing on amniotic fluid cells,fetal tissue,and placental biopsies showed that the fetal karyotype was 47,XXY,while the placenta was a rare mosaic of 47,XY,+21;47,XXY;and 46,XY.CONCLUSION The patient had a rare CPM consisting of 47,XY,+21;47,XXY;and 46,XY,which caused a discrepancy between the result of NIPT and the actual fetal karyotype.It is important to remember that NIPT is a screening test,not a diagnostic test.Any positive result should be confirmed with invasive testing,and routine ultrasound examination is still necessary after a negative result.

2+0 CYP21A2 deletion carrier—a limitation of the genetic testing and counseling:A case report

BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.

Comparison of next generation sequencing-based and methylated DNA immunoprecipitation-based approaches for fetal aneuploidy non-invasive prenatal testing

Over the past few years, many researchers have attempted to develop non-invasive prenatal testing methods in order to investigate the genetic status of the fetus. The aim is to avoid invasive procedures such as chorionic villus and amniotic fluid sampling, which result in a significant risk for pregnancy loss. The discovery of cell free fetal DNA circulating in the maternal blood has great potential for the development of non-invasive prenatal testing(NIPT) methodologies. Such strategies have been successfully applied for the determination of the fetal rhesus status and inherited monogenic disease but the field of fetal aneuploidy investigation seems to be more challenging. The main reason for this is that the maternal cell free DNA in the mother's plasma is far more abundant, and because it is identical to half of the corresponding fetal DNA. Approaches developed are mainly based on next generation sequencing(NGS) technologies and epigenetic genetic modifications, such as fetal-maternal DNA differential methylation. At present, genetic services for non-invasive fetal aneuploidy detection are offered using NGS-based approaches but, for reasons that are presented herein, they still serve as screening tests which are not readily accessed by the majority of couples. Here we discuss the limitations of both strategies for NIPT and the future potential of the methods developed.

Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple:A case report

BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.

Subjective Cognitive Concerns and Attitudes toward Genetic Testing Are Associated with Depressive Symptoms and Quality of Life after Genetic Testing for the Cerebral Cavernous Malformation Common Hispanic Mutation (CCM1)

Purpose: This study aimed to characterize mood and quality of life and to examine the associations of these areas with subjective cognitive concerns and attitudes toward genetic testing for the Common Hispanic Mutation, a gene that has been associated with increased risk for CCM1. Method: Fifty-four adults with previous genetic testing for the Common Hispanic Mutation completed a mail survey that included assessments of the above identified areas. Results: Self-reported depressive symptoms and quality of life did not differ between those with positive and negative genetic test results. The negative group expressed a more favorable attitude toward genetic testing (p p = 0.06). Using generalized linear regression, more subjective cognitive concerns were associated with poorer quality of life and more depressive symptoms (p p Conclusions: Subjective cognitive concerns and negative attitudes toward genetic testing may influence emotional well-being after genetic testing for the Common Hispanic Mutation. Additional research is needed that uses objective neuropsychological measures to understand the associations of subjective cognitive concerns, emotional well-being, and cognitive test performance in individuals with CCM1. There is also a need for research that focuses on protective factors and resiliency following genetic testing for CCM1 and the development of mental health interventions to preempt psychosocial difficulties.

Advances of Genetic Testing Technology in Etiology Diagnosis of Recurrent Spontaneous Abortion

Recurrent spontaneous abortion (RSA) is a complex and heterogeneous disorder with multiple etiologies. Genetic factors are thought to play an important role in the etiology of RSA. With recent advances in genetic testing technologies, there has been an increasing interest in using these tools to diagnose the etiology of RSA. This review discusses the different types of genetic testing methods, such as karyotyping, chromosomal microarray analysis, next-generation sequencing, and their applications in the diagnosis of the etiology RSA. The use of genetic testing in the diagnosis of RSA has the potential to improve the accuracy of diagnosis and the understanding of the underlying mechanisms of the disorder, which could lead to better management and treatment of affected individuals.