Clinical Application Of Genetic Testing Research Articles

The clinical application of genetic testing in DILI, are we there yet?

The clinical application of genetic testing in DILI, are we there yet?

Personalization of clopidogrel therapy based on genetic polymorphism analysis: clinical implications.

This study aimed to evaluate the impact of gene polymorphisms on clopidogrel metabolism and to use this analysis to inform treatment strategy for a population in southern Anhui of China. The research was conducted from 2019 to 2022, aincluding 430 patients from the Wuhu Hospital, affiliated with East China Normal University who were candidates for clopidogrel therapy. Genes influencing clopidogrel's absorption and metabolism were analyzed to guide treatment. Patient data were collected, and genotype and metabolic type distributions were compared. Patients needing medication adjustments were followed up and divided into two groups based on whether they received adjustments or not, and the re-admission rates for antiplatelet therapy within 12 months were compared. The 430 samples showed the expected genotypes and gene distribution, with no significant correlation to age or sex. The CYP2C19 metabolic phenotype frequency was moderate at 57.44%, fast at 25.12%, slow at 15.58%, and ultra-fast at 1.86%. The ABCB1-3435C>T genotype distribution was wild type in 38.14%, heterozygous in 42.33%, and mutant homozygous in 19.53%, with the TT group being significantly younger. The PON1-576G>A genotype showed no significant baseline differences. Of the 279 patients needing medication advice, 39.07% received it. The adjusted group had a significantly lower re-admission rate within one year. The distribution of gene polymorphisms related to clopidogrel metabolism varied within the study population, indicating a potential for personalized medication approaches. The study provides insight into the clinical application of genetic testing for clopidogrel therapy.

Clinical application of genetic testing on operative procedures for hereditary breast ovarian cancer (HBOC) - An identical twins case

Clinical application of genetic testing on operative procedures for hereditary breast ovarian cancer (HBOC) - An identical twins case

Consensus recommendations for the clinical application of genetic testing for children's genetic diseases

儿童是遗传病的主要人群。目前，遗传检测技术已广泛应用在儿科临床中，但尚无相应的应用指南。主要从遗传检测的适应证、常用遗传检测技术和诊断方法的选择、高通量测序报告的解读、遗传咨询、临床决策的建议和伦理等方面，为儿科医生在临床应用中提供指导，本共识旨在为遗传诊断在儿童遗传病的临床实践提供行业的指导。.

Clinical Application of Genetic Testing in Heart Failure.

The purpose of this review is to present our current understanding of the genetic etiologies that may cause or predispose to heart failure. We highlight known phenotypes for which a genetic evaluation has clinical utility. The literature continues to demonstrate and confirm a genetic basis for conditions that cause heart failure. Evidence suggests a genetic model involving rare and common variants of strong or weak effect, in combination with environmental factors that may manifest as familial or simplex disease. Clinical genetic testing is available for several phenotypes, which can aid in the diagnosis and identification of at-risk family members. The evaluation of heart failure should include investigating etiologies with a genetic basis. Conducting a genetic evaluation in patients with heart failure requires the ability to identify possible genetic etiologies in an individual's phenotype, obtain relevant family history, and clinically interpret genetic testing results.

Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.

BackgroundGene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants.MethodsWe use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS‐relevant variants were cross‐checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.”ResultsPublished ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers.ConclusionsThe use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS.

Genotype-guided diagnosis in familial hypercholesterolemia: clinical management and concerns.

In this review, we examine benefits and concerns associated with genetic testing in the clinical management of familial hypercholesterolemia (FH). Application of next-generation sequencing and other advances provide improved yield of causal mutations compared with older methods and help disclose underlying pathophysiology in many instances. Concerns regarding clinical application of genetic testing remain. More widespread application of genetic testing for FH in the USA may be forthcoming. When a genetic cause of FH can be identified or is known for the family, test results can provide more accurate individual diagnosis of FH, clarification of underlying pathophysiology, and greater clinical insight. However, several concerns persist, particularly cost to FH patients, potential discrimination, and inappropriate denial of clinically indicated therapies for patients without definitive genetic testing results.

Arrhythmogenic Right Ventricular Cardiomyopathy: Growing Evidence for Complex Inheritance

The identification of the genetic underpinnings of the rare Mendelian cardiac diseases associated with sudden cardiac death (SCD) in the young has led to an improvement in the management of patients with some of these disorders.1 For example, genetic testing in the long-QT syndrome (LQTS) provides an important means of confirming the clinical diagnosis and allows for cascade familial screening in affected families. Moreover, in this disorder, numerous genotype–phenotype relationships have been uncovered, such as the relation between the affected gene and arrhythmogenic triggers, and genotype-specific response to pharmacotherapy. In the LQTS, genetic testing, which identifies a (putative) mutation in ≈70% of probands, has joined traditional risk factors, such as sex and the extent of QTc-interval prolongation, as an independent prognostic risk factor.1 This contrasts sharply with other disorders associated with SCD in the young, 1 of which is arrhythmogenic right ventricular cardiomyopathy (ARVC), where the role of genotype as a prognostic factor is unclear.1 Article see p 533 ARVC2 is a progressive disease of the myocardium, which leads to cardiomyopathic changes involving pathological fatty infiltration and cardiomyocyte loss and SCD from ventricular arrhythmias at a young age. Although it has classically been considered to affect the right ventricle (hence the name), the increasing awareness of the disease has led to the recognition of forms that present left ventricular or biventricular involvement.2 Genetic studies have identified a number of genes for the disorder; most of these encode components of the cardiac desmosome ( DSC2 , DSG2 , DSP , JUP , and PKP2 ), although other genes have also been implicated (eg, TMEM43 and PLN ). About 50% to 70% of probands harbor a causal or possibly causal mutation in a desmosomal gene.2 However, although gene identification has provided important molecular insight for initiation of mechanistic studies …

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

TEN YEARS OF NEUROGENETIC REQUESTS: TO TEST OR NOT TO TEST?

BackgroundClinical neurology has benefitted significantly from advances in molecular genetics with the discovery of disease–associated genes leading to the clinical application of genetic testing. With an ever increasing arsenal of...

Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder

Numerous studies have reported on pharmacogenetics of antidepressant response in depression. In contrast, little is known of response predictors in obsessive-compulsive disorder (OCD), a disorder with among the lowest proportion of responders to medication (40-60%). Our study is the largest investigation to date (N=184) of treatment response and side effects to antidepressants in OCD based on metabolizer status for CYP2D6 and CYP2C19. We observed significantly more failed medication trials in CYP2D6 non-extensive compared with extensive metabolizers (P=0.007). CYP2D6 metabolizer status was associated with side effects to venlafaxine (P=0.022). There were nonsignificant trends for association of CYP2D6 metabolizer status with response to fluoxetine (P=0.056) and of CYP2C19 metabolizer status with response to sertraline (P=0.064). Our study is the first to indicate that CYP genes may have a role in antidepressant response in OCD. More research is required for a future clinical application of genetic testing, which could lead to improved treatment outcomes.

Use of Genetics in the Clinical Evaluation and Management of Heart Failure

Inherited forms of cardiomyopathy are common causes of heart failure. Applications of genetics in the evaluation and management of heart failure include the determination of inheritance patterns within families with cardiomyopathy, the evaluation of affected patients for syndromic features, the determination of people within families who are at risk of heart failure, and the identification of responsible gene mutations. Family planning may also be assisted by determination of a clear mutation that predisposes to heart failure. Genetic counseling is critical, and it should accompany the use of genetic testing in cardiovascular diseases. With the rapid pace of growth in technology that is used to determine DNA sequence, costs have declined and clinical application of genetic testing has expanded. This is particularly relevant for heart failure, because each of the familial forms of cardiomyopathy may be caused by a mutation in many different genes. Most families share a unique gene mutation, and appropriate interpretation of novel DNA variants is essential for proper use. The evaluation of risk of arrhythmia in familial forms of heart failure may benefit from genetic testing, as mutations in the genes encoding lamin A/C, desmin, and cardiac troponin T are associated with increased risk of sudden cardiac death. Because of its complexity and the rapid rate of change in available genetic testing options, the genetic evaluation of heart failure is best suited to tertiary referral centers with specific expertise in this area.

Genetic testing in clinical pediatric practice

' = Abstract = Completion of the human genome project has allowed a deeper understanding of molecular pathophysiology and has provided invaluable genomic information for the diagnosis of genetic disorders. Advent of new technologies has lead to an explosion in genetic testing. However, this overwhelming stream of genetic information often misleads physicians and patients into a misguided faith in the power of genetic testing. Moreover, genetic testing raises a number of ethical, legal, and social issues. Diagnostic genetic tests can be divided into three primary but overlapping categories: cytogenetic studies (including routine karyotyping, high-resolution karyotyping, and fluorescent in situ hybridization studies), bioche- mical tests, and DNA-based diagnostic tests. DNA-based testing has grown rapidly over the past decade and includes pre- and postnatal testing for the diagnosis of genetic diseases, testing for carriers of genetic diseases, genetic testing for susceptibility to common non-genetic diseases, and screening for common genetic diseases in a particular population. Theoretically, once a gene's structure, function, and association with a disease are well established, the clinical application of genetic testing should be feasible. However, for routine applications in a clinical setting, such tests must satisfy a num- ber of criteria. These criteria include an acceptable degree of clinical and analytical validity, support of a quality assurance program, possibility of modifying the course of the diagnosed disease with treatment, inclusion of pre-and postnatal ge- netic counseling, and determination of whether the proposed test satisfies cost-benefit criteria and should replace or com- plement traditional tests. In the near future, the application of genetic testing to common diseases is expected to expand and will likely be extended to include individual pharmacogenetic assessments. (Korean J Pediatr 2010;53:273-285)

The clinical application of genetic testing in type 2 diabetes: a patient and physician survey.

Advances in type 2 diabetes genetics have raised hopes that genetic testing will improve disease prediction, prevention and treatment. Little is known about current physician and patient views regarding type 2 diabetes genetic testing. We hypothesised that physician and patient views would differ regarding the impact of genetic testing on motivation and adherence. We surveyed a nationally representative sample of US primary care physicians and endocrinologists (n = 304), a random sample of non-diabetic primary care patients (n = 152) and patients enrolled in a diabetes pharmacogenetics study (n = 89). Physicians and patients favoured genetic testing for diabetes risk prediction (79% of physicians vs 80% of non-diabetic patients would be somewhat/very likely to order/request testing, p = 0.7). More patients than physicians (71% vs 23%, p < 0.01) indicated that a 'high risk' result would be very likely to improve motivation to adopt preventive lifestyle changes. Patients favoured genetic testing to guide therapy (78% of patients vs 48% of physicians very likely to request/recommend testing, p < 0.01) and reported that genetic testing would make them 'much more motivated' to adhere to medications (72% vs 18% of physicians, p < 0.01). Many physicians (39%) would be somewhat/very likely to order genetic testing before published evidence of clinical efficacy. Despite the paucity of current data, physicians and patients reported high expectations that genetic testing would improve patient motivation to adopt key behaviours for the prevention or control of type 2 diabetes. This suggests the testable hypothesis that 'genetic' risk information might have greater value to motivate behaviour change compared with standard risk information.

Can geneticists help clinicians to understand and treat non-autoimmune diabetes?

Approximately, a few percent of the European population suffers from diabetes. Scientific evidence showed that specific treatment of this disease could be successfully tailored on the basis of proper differential diagnosis that in many instances also requires genetic testing. This may be helpful in achieving metabolic control of the disease, increasing quality of life and potentially reducing the prevalence of chronic complications. Identification of the molecular background of these specific forms of diabetes gives new insight into the underlying aetiology. This knowledge helps to optimize treatment in specific clinical situations. Monogenic diabetes is an excellent example of a clinical area where new advances in molecular genetics can aid patient care and treatment decisions. The most frequently diagnosed forms of monogenic diabetes are MODY, mitochondrial diabetes, permanent and transient neonatal diabetes (PNDM and TNDM). These rare forms probably constitute at least a few percent of all diabetes cases seen in diabetic clinics. The proper differential diagnosis also helps to predict the progress of diabetes in affected individuals and defines the prognosis in the family. Recently, several genome wide association studies added new facts to the knowledge on complex forms of type 2 diabetes mellitus (T2DM) as the scientists substantially extended the short list of previously identified genes. Most newly identified variants influence β-cell insulin secretion, while a few modulate peripheral insulin action. It is not clear whether in the future the genetic testing of frequent polymorphisms will influence the treatment of T2DM. In this review, we present the clinical application of genetic testing in non-autoimmune diabetes, mostly monogenic forms of disease.

Clinical Application of Genetic Testing

The completion of the human genome project enables us to understand the molecular pathophysiology of human genetic diseases more deeply. In addition, information from genomics has been utilized for the diagnosis of genetic disorders. The technological innovations have been explosive in the field of genetic testing. However, overwhelming genetic information often misleads physicians as well as patients to a wrong belief in the power of genetic testing. Genetic testing implicates many issues such as ethical, legal and social issues. Diagnostic genetic tests can be divided into three primary but overlapping categories: cytogenetic studies (including routine karyotyping, high-resolution karyotyping, and fluorescent in situ hybridization (FISH) studies], biochemical tests, and DNA-based diagnostic tests. DNA-based testing has grown rapidly over the last decade and includes pre- and postnatal genetic testing for the diagnosis of Mendelian diseases in patients, carrier testing, the determination of individual susceptibility to common complex diseases, and population screening of common genetic diseases in a particular population. Theoretically, once the structure, function, and disease association of a gene are well clarified, the clinical application of the genetic testing seems to be feasible. However, the test has to satisfy certain criteria for clinical application at a routine clinical setting; a high sensitivity and positive predictive values, the availability of a controllable quality assurance program, the determination of whether the test is replacing or is complementary to the traditional test, a cost-benefit issue, the possibility of treatment or disease-course modification, possible pre-and postnatal genetic counseling, and so on. In the near future, the application of genetic testing will be further expanded to common diseases and the pharmacogenetic assessment of individuals.

Mutations in TRIOBP, Which Encodes a Putative Cytoskeletal-Organizing Protein, Are Associated with Nonsyndromic Recessive Deafness

In seven families, six different mutant alleles of TRIOBP on chromosome 22q13 cosegregate with autosomal recessive nonsyndromic deafness. These alleles include four nonsense (Q297X, R788X, R1068X, and R1117X) and two frameshift (D1069fsX1082 and R1078fsX1083) mutations, all located in exon 6 of TRIOBP. There are several alternative splice isoforms of this gene, the longest of which, TRIOBP-6, comprises 23 exons. The linkage interval for the deafness segregating in these families includes DFNB28. Genetic heterogeneity at this locus is suggested by three additional families that show significant evidence of linkage of deafness to markers on chromosome 22q13 but that apparently have no mutations in the TRIOBP gene.

Clinical application of genetic testing for deafness.

Advances in the molecular biology of hearing and deafness have identified many genes essential for normal auditory function. Allele variants of these genes cause nonsyndromic deafness, making mutation screening a valuable test to unequivocally diagnose many different forms of inherited deafness. In this study, genetic testing of GJB2, SLC26A4 and WFS1 is reviewed.