Genetic Testing In Clinical Practice Research Articles

Familial states of primary hyperparathyroidism: an update.

Familial primary hyperparathyroidism (PHPT) includes syndromic and non-syndromic disorders. The former are characterized by the occurrence of PHPT in association with extra-parathyroid manifestations and includes multiple endocrine neoplasia (MEN) types 1, 2, and 4 syndromes, and hyperparathyroidism-jaw tumor (HPT-JT). The latter consists of familial hypocalciuric hypercalcemia (FHH) types 1, 2 and 3, neonatal severe primary hyperparathyroidism (NSHPT), and familial isolated primary hyperparathyroidism (FIHP). The familial forms of PHPT show different levels of PHPT penetrance, developing earlier and with multiglandular involvement compared to sporadic counterpart. All these diseases exhibit Mendelian inheritance patterns, and for most of them, the genes responsible have been identified. DNA testing for predisposing mutations is helpful in index cases or in individuals with a high suspicion of the disease. Early recognition of hereditary disorders of PHPT is of great importance for the best clinical and surgical approach. Genetic testing is useful in routine clinical practice because it will also involve appropriate screening for extra-parathyroidal manifestations related to the syndrome as well as the identification of asymptomatic carriers of the mutation. The aim of the review is to discuss the current knowledge on the clinical and genetic profile of these disorders along with the importance of genetic testing in clinical practice.

Genetic Testing of Movements Disorders: A Review of Clinical Utility.

The utility of genetic testing extends across multiple clinical and non-clinical domains. Here we review different aspects of the utility of genetic testing for movement disorders and the numerous associated challenges and limitations. These factors should be weighed on a case-by-case basis when requesting genetic tests in clinical practice.

Incidence of amyotrophic lateral sclerosis-associated genetic variants: a clinic-based study.

This study is to determine the incidence of genetic forms of amyotrophic lateral sclerosis (ALS) in clinic-based population. Next-generation sequencing (NGS) of whole exome sequencing (WES) was conducted among a total of 374 patients with definite or probable ALS to identify ALS-associated genes based on ALSoD database ( https://alsod.ac.uk ) [2023-07-01]. Variants of ALS-associated genes were detected in 54.01% (202/374) ALS patients, among which 8.29% (31/374) were pathogenic/likely pathogenic (P/LP). The detection rates of P/LP variants were significantly higher in familial ALS than sporadic ALS (42.31% vs 5.75%, p < 0.001), while VUS mutations were more commonly detected in sporadic ALS (23.07% vs 47.13%, p = 0.018). There is no significant difference in detection rate between patients with and without early onset (8.93% vs 7.77%), rapid progression (9.30% vs 8.91%), cognitive decline (15.00% vs 7.93%), and cerebellar ataxia (20.00% vs 8.15%) (p > 0.05). Over half of our ALS patients carried variants of ALS-related genes, most of which were variants of uncertain significance (VUS). Family history of ALS could work as strong evidence for carrying P/LP variants regarding ALS. There was no additionally suggestive effect of indicators including early onset, progression rate, cognitive decline, or cerebellar ataxia on the recommendation of genetic testing in clinical practice.

Attention should be paid to the importance of genetic testing in clinical practice of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS) is a progressive and fatal neurodegenerative disease that mainly involves upper and lower motor neurons. It lacks clear biomarkers and can be clearly diagnosed only one and a half years after the onset. Gene test is of great significance for diagnosis, prognosis and genetic counseling. In recent years, several gene therapy studies have entered the clinical trial stage of ALS, among which the antisense oligonucleotide therapy targeting the pathogenic variation of the superoxide dismutase 1 (SOD1) gene has been launched, and it is urgent to carry out routine gene test in clinical practice. On the basis of progress of ALS gene research in recent years, family history, age of onset and typical clinical manifestations of patients are no longer considered as the basis for genetic testing. However, the target genes of clinical gene testing needs to be further clarified according to the diagnostic purpose, the testing method and scheme need to be standardized, and the genetic consultation before testing should be paid attention to, and the informed consent should be fully achieved.

Knowledge, attitude, and perceptions about cancer genetic testing in clinical practice in Karachi, Pakistan.

Healthcare professionals (HCP) play an important role in the practical application of genetic screening tests but often feel inadequately prepared for cancer genetic testing (CGT) in clinical care. As the complexity of gene-related malignancies increases, it demands HCPs' preparedness to cater to patients' needs. Therefore, the aim of our study is to assess the knowledge, attitude, and practices of HCPs in Pakistan regarding the application of cancer genetics. Our cross-sectional survey was conducted from April 2022 to June 2022 amongst HCPs at a private and a governmental institution in Karachi, Pakistan. Non-probability random convenience sampling was used to select the population; however. non-clinical HCPs, as well as Interns, were excluded from our study. A total of 210 HCPs, 56.7% (119) bearing an experience of over 5years of clinical experience, were included in this study. Most respondents from both hospitals deemed their knowledge inadequate, with only 2% (2) and 1.8% (2) being extremely knowledgeable, respectively. 68.6% (144) HCPs displayed a positive attitude towards CGT, with 55.2% (116) participants perceiving CGT in a positive light. As compared to the private sector, significantly more HCPs in the public sector dedicated ≥ 5h/week for CME (P = 0.006), and were better prepared to counsel patients (P = 0.021) and interpret results concerning CGT (P = 0.020). Additionally, screening tests for specific cancer types were popularly considered a worthwhile avenue of investment to improve the current state of CGT in our healthcare system [47.6% (N = 100)]. Demonstrating a lack of knowledge among Pakistani doctors, our results call upon the need for additional training concerning CGT in both the public and private sectors alike. Understanding specific gaps in knowledge may further help enhance post-graduate training programs and eventually lead to effective incorporation of CGT into our healthcare setting.

Genetic Testing in Clinical Movement Disorders: A Case-Based Review.

Genetics are fundamental to understanding the pathophysiology of neurological disease, including movement disorders. Genetic testing in clinical practice has changed dramatically over the last few decades. While the likelihood of establishing an etiological diagnosis is greater now with increased access to testing and more advanced technologies, clinicians face challenges when deciding whether to test, then selecting the appropriate test, and ultimately interpreting and sharing the results with patients and families. In this review, we use a case-based approach to cover core aspects of genetic testing for the neurologist, namely, genetic testing in Parkinson's disease, interpretation of inconclusive genetic test reports, and genetic testing for repeat expansion disorders using Huntington disease as a prototype.

A CASE OF DILATED CARDIOMYOPATHY CAUSED BY TNNT2 MUTATION

Dilated cardiomyopathy is one of the leading causes of heart failure with high morbidity and mortality. Although more than 40 genes have been reported to cause dilated cardiomyopathy, the role of genetic testing in clinical practice is not well defined. Mutations in the troponin T (TNNT2) gene represent an important subset of known disease-causing mutations associated with dilated cardiomyopathy. Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy. This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset dilated cardiomyopathy. Further, the trigger for late onset dilated cardiomyopathy remains enigmatic. Here, we presented a case of dilated cardiomyopathy caused by TNNT2 mutation in 59-year-old male.

RESEARCH INSTITUTE: CHILD AND ADOLESCENT PSYCHIATRY IN THE ERA OF GENOMICS

This Research Institute aims to introduce clinicians to cutting-edge research in the genetics of child mental health disorders and discuss the emerging role of genetic tests in clinical practice. The goals of this Institute are to: 1) highlight emerging research in the genetics and genomics of child mental health disorders; and 2) advance clinicians’ knowledge of ways in which genetic testing can begin to inform clinical diagnosis and management.

Diagnostic Outcome of Genetic Testing for Neuromuscular Disorders in a Tertiary Center.

Genetic testing is an effective and reliable modality in clinical neuromuscular diagnosis. The recent developments in testing methods and increasing reliance on genetic testing in clinical practice require more studies to examine the benefits and advantages of such tests. We examined the results of single-gene sequencing/repeat analysis, panels, and whole-genome sequencing (WES) of 514 tests of 393 patients. All patients were suspected of a neuromuscular disorder and the samples were either WBC or muscle tissue. 28.60% (n.147) of the tests were positive while 23.74% (n.122) were VUS. In single-gene sequencing/repeat analysis, 43.08% were positive, in panels, 23.17% were positive, while 30.00% were positive in WES. Our results showed consistency with current studies and improvement of the utility of genetic testing. Although some obstacles are identified, providing statistical data can support more usage and popularity of genetic testing among physicians and patients.

The First Baby Born After Polygenic Embryo Screening

The First Baby Born After Polygenic Embryo Screening

Helix: A Digital Tool to Address Provider Needs for Prostate Cancer Genetic Testing in Clinical Practice

Prostate cancer (PCA) germline testing (GT) is now standard-of-care for men with advanced PCA. Thousands of men may consider GT due to clinical and family history (FH) features. Identifying and consenting men for GT can be complex. Here we identified barriers and facilitators of GT across a spectrum of providers which informed the development of Helix - an educational and clinical/FH collection tool to facilitate GT in practice. A 12-question survey assessing knowledge of genetics PCA risk and FH was administered December 2017 to March 2018 in the Philadelphia area and at the Mid-Atlantic AUA meeting (March 2018). Responses were analyzed using descriptive statistics. Semi-structured interviews were conducted with medical oncologists, radiation oncologists, and urologists across practice settings from March-October 2020 as part of a larger study based on the Tailored Implementation in Chronic Diseases framework. Helix was then developed followed by user testing. Fifty-six providers (50% urologists) responded to the survey. Multiple FH and genetic knowledge gaps were identified: only 66% collected maternal FH and 43% correctly identified BRCA2 and association to aggressive PCA. Genetic counseling gaps included low rates of discussing genetic discrimination laws (45%). Provider interviews (n = 14) identified barriers to FH intake including access to details and time needed. In user testing (n = 10), providers found Helix helpful for FH collection. All providers found Helix easy to use, suggesting expanded clinical use. Helix addressed multiple GT knowledge and practice gaps across a spectrum of providers. This tool will become publicly available soon to facilitate PCA GT in clinical practice.

Genetic Testing in Patients with High Lipoprotein(a): Experience from the UCSD Lipoprotein(a) Specialty Clinic†

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis Lipoprotein(a) (Lp(a)) is an inherited and likely causal risk factor for cardiovascular disease (CVD) and aortic stenosis. LPA variants rs10455872 and rs3798220 are present in ∼15% and ∼3% of Caucasians, respectively, and are associated with elevated Lp(a) levels. Genetic testing in clinical practice is emerging as a tool for personalizing risk assessment and treatment decisions [1-3]. Objective/Purpose To explore the role of genetic testing for LPA SNPs and other genetic mutations in patients with elevated Lp(a). Methods In the UC San Diego Lipoprotein(a) Specialty Clinic, next-generation DNA sequencing was performed using the GBinsight Comprehensive Dyslipidemia Panel (GB Lifesciences, San Diego, CA, USA) in 26 patients with Lp(a) ³ 50 mg/dL, evaluating 327 exons and selected single-nucleotide polymorphisms (SNPs) in 129 genes known or suspected to be associated with CVD. Known LPA SNPs and high impact variants in other genes associated with lipid abnormalities were reported as pathogenic/likely pathogenic. Given non-normality, Lp(a) values were compared using a Mann-Whitney U test. Results Among the 26 patients (mean age 61 yrs, 50% women), 14 (53.8%) had LPA SNPs that have been shown to be associated with elevated Lp(a): rs10455872 (minor allele frequency (MAF) 2.2%) occurred in 9 patients (34.6%), and rs3798220 (MAF 5.1%) occurred in 7 patients (26.9%). Two patients (7.7%) had both rs10455872 and rs3798220 LPA SNPs. LPA SNP rs41272112 (MAF 2.2%) was present in 1 patient (3.8%), and rs186696265 (MAF 0.3%) was present in 4 patients (15.4%). Thus, 12 patients (46.2%) with elevated Lp(a) had no known LPA SNPs. Three of those 12 patients had other potential genetic explanations for elevated Lp(a) (compound heterozygote LDLR, APOE e4 homozygote, and a heterozygous likely pathogenic variant in LDLRAP1) (Table). Patients with elevated Lp(a) and at least 1 LPA variant had Lp(a) 166 +/- 92 mg/dL (mean+/-SD) (131.5, 106.75-243 mg/dL (median, IQR)), and those with elevated Lp(a) but without an LPA variant had Lp(a) 105.9 +/- 46 mg/dL (mean+/-SD) (100.5, 65.5-127.25 mg/dL (median, IQR) (p=0.08)). Conclusions Real-world testing for LPA SNPs in a referral Lp(a) specialty practice demonstrates genetic associations of elevated Lp(a) in approximately half of the patients, which is substantially higher than the general population. However, a significant proportion of patients have no known LPA SNPs despite highly elevated Lp(a), suggesting they harbor small apo(a) isoforms. The role of genetic testing at the bedside in such patients is evolving. A dedicated Lp(a) specialty clinic may allow optimal evaluation and management of patients with elevated Lp(a). Nothing to disclose.

Genetic Testing for Antipsychotic Pharmacotherapy: Bench to Bedside

There is growing research interest in learning the genetic basis of response and adverse effects with psychotropic medications, including antipsychotic drugs. However, the clinical utility of information from genetic studies is compromised by their controversial results, primarily due to relatively small effect and sample sizes. Clinical, demographic, and environmental differences in patient cohorts further explain the lack of consistent results from these genetic studies. Furthermore, the availability of psychopharmacological expertise in interpreting clinically meaningful results from genetic assays has been a challenge, one that often results in suboptimal use of genetic testing in clinical practice. These limitations explain the difficulties in the translation of psychopharmacological research in pharmacogenetics and pharmacogenomics from bench to bedside to manage increasingly treatment-refractory psychiatric disorders, especially schizophrenia. Although these shortcomings question the utility of genetic testing in the general population, the commercially available genetic assays are being increasingly utilized to optimize the effectiveness of psychotropic medications in the treatment-refractory patient population, including schizophrenia. In this context, patients with treatment-refractory schizophrenia are among of the most vulnerable patients to be exposed to the debilitating adverse effects from often irrational and high-dose antipsychotic polypharmacy without clinically meaningful benefits. The primary objective of this comprehensive review is to analyze and interpret replicated findings from the genetic studies to identify specific genetic biomarkers that could be utilized to enhance antipsychotic efficacy and tolerability in the treatment-refractory schizophrenia population.

Recent Insights on Genetic Testing in Primary Prostate Cancer.

Prostate cancer (PCa) is one of the most common cancers in developed countries. The results of large trials indicate that the proportion of PCa attributable to hereditary factors is as high as 15%, highlighting the importance of genetic testing. Despite improved understanding of the prevalence of pathogenic variants among men with PCa, it remains unclear which men will most benefit from genetic testing. In this review, we summarize recent evidence on genetic testing in primary PCa and its impact on routine clinical practice. We outline current guideline recommendations on genetic testing, most importantly, for mutations in BRCA1/2, MMR, CHEK2, PALB2, and HOXB13 genes, as well as various single nucleotide polymorphisms associated with an increased risk of developing PCa. The implementation of genetic testing in clinical practice, especially in young patients with aggressive tumors or those with positive family history, represents a new challenge for the coming years and will identify men with pathogenic variants who may benefit from early screening/intervention and specific therapeutic options.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-021-00529-3.

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

Introduction and hypothesisFamily and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations.MethodsUpdating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria.ResultsWe screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46–0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11–1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39–0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66–0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies.ConclusionThe genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.

‘More than a box of puzzles’: Understanding the parental experience of having a child with a rare genetic condition"

BackgroundChromosomal microarray (CMA) testing has been adopted as the first-tier diagnostic test for developmental disabilities. However, determining the clinical significance of the results is often complex. This qualitative study seeks to explore parental interpretation, adaption and coping in the context of ambiguous rare genetic findings in order to support parental adjustment and wellbeing. MethodsIn-depth interviews were conducted with parents (n = 30) of children identified with a rare genetic chromosomal abnormality. ResultsThree major themes were identified following a thematic analysis: ‘Learning of the Genetic Diagnosis', “The Reality of the Rarity’ and ‘Beyond Genetics: The Child Takes Centre Stage’. Findings demonstrated that parental adjustment to their child's genetic results are mediated by several factors including child difficulties and stage of development, clinician communication, perception of genetics, intrinsic coping strategies, access to practical and emotional support as well as broader contextual experiences. ConclusionThis study highlights the importance of considering the parental perspective in the context of genetic testing in clinical practice.

Új lehetőség a szisztolés szívelégtelenség (HFrEF) kezelésében: omecamtiv-mecarbil

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

Genetic diagnosis in hypertrophic cardiomyopathy: two steps forward, one step back

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder worldwide which exhibits considerable genetic heterogeneity. Widespread utilization of next-generation sequencing (NGS) in HCM has uncovered substantial genetic variation and highlighted the importance of a standardized approach to variant interpretation. According to this, accurate and consistent interpretation of sequence variants is essential for effective clinical care for individuals and their families with HCM. With this regard, the 2015 guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) were widely applicable, but several elements lacked specificity for given genes or diseases. The latter guideline was adapted for the most frequent causative HCM gene, the beta myosin heavy chain gene (MYH7) by the ClinGen (Clinical Genome Resource) expert panel, the Inherited Cardiomyopathy Expert Panel. Due to the adaptation, the guideline became gene-specific, with general considerations which are widely adaptable for most of the causative genes in HCM. Based on the modified guideline, web-based interpretation algorithms have been developed which integrate data from population databases and define pathogenicity of different variants independent of the observer, therefore aiding standardized clinical interpretation of genetic testing. The latter approach serves as a basis for recommendation for genetic testing in the recent ACC/AHA HCM guideline published in 2020. The current review is meant to compile the latest advances in HCM genetic testing in clinical practice, while bringing into focus some of the ongoing challenges clinical geneticists are still facing. Although nowadays the interpretation of genetic findings is two steps closer to a more accurate approach due to gene adaptation and automatization, the multitude of putative causative genes have been once again reduced to the 8 sarcomere genes, a backward step.

What Do Students in Pharmacy and Medicine Think About Pharmacogenomics and Personalized Medicine Education? Awareness, Attitudes, and Perceptions in Malaysian Health Sciences.

This study reports on the attitudes and perceptions toward pharmacogenomics (PGx) and personalized medicine (PM) education among pharmacy and medical students in Malaysian health sciences. Importantly, the survey was developed through a codesign approach, with field pretesting/design with users before the actual survey, and based on collaboration between institutions in Greece and Malaysia. The study addressed eight key areas of interest to education in health sciences: (1) General awareness about genetics and PGx, (2) Attitude toward genetic testing usefulness, (3) Benefits of direct-to-consumer personal genome testing as a "diagnostic" tool, (4) Concerns (risks) about genetics, (5) Effectiveness of genetic testing in PM, (6) Benefits of PGx on disease management, (7) Benefits of PGx on drug management, and (8) Attitudes toward genetic testing public endorsement. We observed that Malaysian students appear aware of the term PGx, but there are areas of critical knowledge gap such as the need for greater familiarity with the concept of PGx implementation science, and the availability of genetic testing in clinical practice. This is one of the first studies on perceptions and attitudes toward PGx testing in Southeast Asia. The present findings provide a map of the views and perspectives of medicine and pharmacy students regarding PGx and implementation of PM in Malaysia and should assist toward facilitating the integration of genomics into the medical decision-making process. To this end, it is necessary to enhance collaboration between universities, health care institutions, and governing bodies to incorporate further training and additional education topics related to PGx and genetic testing. This is the first study that assesses the level of PGx and genomics knowledge of pharmacy and medicine students in Southeast Asia, Malaysia in particular, and thus paves the way to guide future global PGx implementation science.

Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development

ABSTRACTIntroduction: Over a decade of research and development culminated in the 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN) for RPE65 mutation-associated inherited retinal disease (IRD), the first approved gene therapy for a hereditary genetic disease in the US, and the first and only pharmacologic treatment for an IRD.Areas covered: VN serves as a model for ocular gene therapy development, while RPE65 mutation-associated IRD serves as an example of a well-suited candidate disorder. This review also discusses development considerations for viral vector gene augmentation, and, studies that led to VN’s FDA approval. Subretinal injection of VN resulted in improved performance on the novel multi-luminance mobility test (MLMT), light sensitivity, and visual fields in patients with RPE65 mutation-associated IRD, which predominantly impairs rod function. Additionally, the dosage, administration technique, pharmacokinetics, and safety data of VN are reviewed.Expert Opinion: As a model for development, special challenges associated with the introduction of this first ocular gene therapy include limited genetic testing in clinical practice, novel surgical complexity of ocular gene therapy administration, new functional vision endpoints, as well as unique development, launch, and reimbursement considerations associated with orphan therapies and one-time gene therapies.