Effects Of Genetic Testing Research Articles

Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022

BackgroundCancer Predisposition Syndromes (CPSs) have been identified in 7–15 % of children with cancer. The possibilities for germline genetic testing have increased in recent years, presenting new opportunities but also challenges. There is currently no consensus on germline genetic testing in children with cancer in diagnostic settings. MethodsThe International Society of Pediatric Oncology Europe (SIOPE) Host Genome Working Group used a consensus development conference method to reach agreement on four key topics: Who do we test? Which genes do we test? What do we disclose? How do we evaluate the benefits of testing? ResultsThe Working Group members agreed that: (1) All children with cancer should undergo clinical screening for their risk of harboring a CPS. (2) Targeted genetic testing based on clinical indication is recommended. Comprehensive CPS gene panels with more than 100–150 genes for all children with cancer should preferably be evaluated within research settings. (3) Smaller actionable gene panels can be considered including genes supporting diagnosis or influencing treatment decisions. (4) Clear pre-test information and consenting processes that highlight potential outcomes and implications of germline genetic testing are imperative. (5) Consequences of genetic testing, treatment adaption, and tumor surveillance in children with CPSs, including economic impact and psychosocial factors, should be further explored. ConclusionsThese consensus-based recommendations provide guidance on germline genetic testing in children with cancer. Regular review of these recommendations is essential. Collaboration and the use of data sharing platforms can further improve screening procedures and its impact on care.

Variants of SERPINA1 and the increasing complexity of testing for alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein. Currently, over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease. The types of these pathogenic mutations are varied, often resulting in misfolding, or truncating of the AAT amino acid sequence, and improvements in sequencing technology are helping to identify known and novel genetic variants. However, due to the diversity and novelty of rare variants, the clinical significance of many is largely unknown. There is, therefore, a lack of guidance on how patients should be monitored and treated when the clinical significance of their variant combination is unclear or variable. Nevertheless, it is important that physicians understand the advantages and disadvantages of the different testing methodologies available to diagnose AATD. Owing to the autosomal inheritance of the genetic mutations responsible for AATD, genetic testing should be offered not only to patients at increased AATD risk (e.g. patients with chronic obstructive pulmonary disease), but also to relatives of those with an abnormal result. Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family. While stress/anxiety can arise from genetic diagnosis or confirmation of carrier status, there can be positive consequences to genetic testing, including improved lifestyle choices, directed medical care, and empowered family planning. As genetic testing technology grows and becomes more popular, testing without physician referral is becoming more prevalent, irrespective of the availability of genetic counseling. Therefore, the Alpha-1 Foundation offers genetic counseling, as well as other support and educational material, for patients with AATD, as well as their families and physicians, to help improve the understanding of potential benefits and consequences of genetic testing.

Effect of Genetic Testing on Diagnosing Gastrointestinal Pediatric Patients with Previously Undiagnosed Diseases.

PurposeFour consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis.Patients and MethodsMembers from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation.ResultsWe had a 100% success rate identifying each case presented in this study.ConclusionThis is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.

Effect of genetic testing results on patient-reported quality of life among patients undergoing panel testing for newly diagnosed ovarian cancer.

1584 Background: This study compared patient-reported stress, anxiety, and depression between newly diagnosed ovarian cancer patients with pathogenic genetic testing results versus patients with non-informative results (i.e., variants of uncertain significance (VUS) or negative). Methods: Patients underwent genetic testing (GT) via a facilitated referral pathway (Frey et al, Gynecol Oncol 2020) through which they were referred for genetic counseling and GT by their gynecologic oncologist within six weeks of diagnosis from 10/2015 to 5/2019. English-speaking patients completed three quality of life (QoL) instruments: Impact of Events Scale (IOES), State-Trait Anxiety Questionnaire (STAI), Hospital Anxiety and Depression Scale (HADS) immediately pre-and post-GT and 6 months post GT. Two-way mixed ANOVA was performed to analyze effect of GT results on QoL over time with significance p < 0.05. Results: One hundred ten patients were enrolled in the pathway and 83 (76%) patients underwent GT. Among these, 15 (18%) had potentially actionable pathogenic mutations ( BRCA1-8, BRCA2-4, MSH2-2, MRE11A-1); 26 (31%) had VUS results; 3 (4%) had both a pathogenic mutation and a VUS result; and 42 (51%) had negative results. Sixty patients (72%) completed QoL assessments pre and post GT, and 37 (44%) patients at 6-9 months post GT. For all patients, GT results did not affect QoL scales across our time points. By mean scores across all-comers, patients demonstrated mild stress at each time point and clinically significant anxiety immediate post-GT. All patients had a statistically significance decrease in HADS depression scores over time from pre-GT to 6 months post-GT (mean score 4.98 vs 2.97, p = 0.020). Patients with VUS had lower HADS mean anxiety scores across time (3.62) compared to patients with pathogenic (7.44) or negative mutations (6.83, p = 0.029). For patients without mutations, there was a significant decrease in clinically significant anxiety by STAI-state score at 6 months (p = 0.002) and a decrease in borderline anxiety by HADS scores at 6 months (p = 0.005). This effect was not present for patients with pathogenic mutations or VUS. Conclusions: A pathogenic result does not impact QoL scales immediately pre or post GT or at 6 months post GT, though patients with negative mutations were more likely to show a decrease in anxiety over time. Patients should be recommended GT at time of diagnosis of ovarian cancer without concern of increased stress, anxiety, or depression based on GT results.

Islamic Ethics and the Legitimacy of Scientific Innovation

This paper examines bioethical discourses concerning genetic counseling within the area of assisted reproduction. More particularly, it investigates the extent to which mainstream Western or secular bioethics is considered lacking from an Islamic perspective. The paper argues that invocation, incorporation, and even interrogation of Islamic norms ensure the legitimacy of genetic counseling within the Muslim context. The paper suggests a distinction between two levels of analysis within Islamic bioethical discussions on the consequences of genetic testing. The first addresses ethical-legal dimensions and is primarily concerned with balancing immediate benefits and harms in this world. The second addresses theological and metaphysical dimensions and is primarily concerned with faith-based convictions and religious commitments. The paper argues that both levels are needed for a nuanced understanding of the process of genetic counseling within a Muslim setting. The paper gives special attention to institutional fatwas on two main issues: prenatal genetic screening and preimplantation genetic diagnosis.

Effect of Genetic Testing for Mental Disorders on Married Couple and Their Reproductive Decisions

Effect of Genetic Testing for Mental Disorders on Married Couple and Their Reproductive Decisions

Development of a telegenetics program in the Asia-Pacific/Middle East region.

15 Background: BRCA mutations is emerging as an agnostic marker for PARPi. Accessibility to genetic counselling is limited due to shortage of manpower and access to institutions that provide it. Our aim was to look at the incidence of pathogenic germline mutations in India/UAE and develop a virtual pathway, aimed at increasing accessibility to genetic counselling. Methods: 864 patients(pts) were tested in the UAE and India for germline mutations. Based on discussion between physicians and patients, an urgent need for genetic counseling was identified. A virtual platform (telegenetics) was constructed for those who sought genetic counseling due to a personal or family history of malignancies. Referral of pts was either self-based or through a treating physician. Primary goals included 1) ease of access for pts, 2) increase comprehension of the indications, implications and consequences of genetic testing, 3) decrease physician time in the clinic. 10 questions were developed determine pt and physician satisfaction. Results: 241(28.9%)pts had a pathogenic variant in BRCA1/BRCA. 115pts were enrolled in the pilot phase of the tele genetics program; all physician referred. Counselling was by a dedicated trained genetic counsellor through voice-call(43.5%), video-conferencing(47.8%) or in person when requested (8.7%). All pts completed a satisfaction survey. Majority of pts were comfortable sharing information on a virtual platform(80%), were happy with the quality of virtual connection(85%), and felt comfortable connecting with the genetic counselor(90%). Information is currently being collected from referring physicians. Conclusions: Our ongoing pilot phase reveals improved pt satisfaction and understanding of the information provided. A mobile application has been developed to enhance pt accessibility/convenience and physician connectivity with the testing phase of the app currently on going. To our knowledge this is the first tele genetics program to target the middle east/Asia pac region that is targeted to cope with increase in pt volumes, expand appropriate referrals, starting with pts who have a personal or family history of cancers, expanding to more complex high risk diseases over time.

1171-P: Effect of Genetic Testing for Weight Loss on Adult Patients

Background: It is well-known in obesity research and clinical practice that there are differing responses to dietary interventions. Genetic evaluation based on metabolic genotypes has been found helpful in understanding which dietary and activity recommendations are a best fit for weight management. Purpose: This study provided information on practicality, acceptability, and effectiveness of incorporating Genetic Influenced to Personalize Dietary and Exercise Plans (GIPDEP) in clinical practice. We assessed the efficacy of personalized weight loss recommendations based on genetic information compared to conventional care. Sample: Patients (N=92; on average 47 years of age [range: 22 to 71]; 78 females; 3 with normal weight, 27 overweight, 62 obese) from a community-based weight loss clinic were randomly assigned to the treatment (51 received genotype test screening) and the control (40 received conventional care) groups stratified by age, gender, initial BMI, and score in the Weight Efficacy Lifestyle (WEL) scale. Measures: The Weight Efficacy Lifestyle questionnaire ([WEL] was used to assess confidence in ability to lose weight. Patients were assessed twice (beginning, 4-month follow-up). Results: At four months, both groups showed comparable decrease in BMI (treatment: Δ(ΒΜΙ)=-0.87±2.06; control: Δ(ΒΜΙ)=-0.81±1.54; Wilcoxon Rank Sums test, p=0.908). Multiple regression was used to assess the effect of treatment on Δ(ΒΜΙ) adjusting for age, gender, exercise, health issues limiting exercise, and daily sleep. In all models, treatment was not a statistically significant predictor of Δ(ΒΜΙ) (all p > 0.50). Summary: Results do not provide evidence that weight loss recommendations based on genetic screening are more advantageous than conventional recommendations. The non-finding may be explained if we consider that weight loss is associated with a number of factors, i.e., self-efficacy, support, etc. The advantage of optimal recommendations may be masked by these other factors. Disclosure K.S. James: None. Funding Allen Foundation Inc.

Metastatic Prostate Cancer: Effects of Genetic Testing on Care.

The National Comprehensive Cancer Network now recommends BRCA1/2 genetic testing in men with metastatic prostate cancer. The purpose of this article is to provide a review of principles of genetic testing in prostate cancer and highlight the significance of clinical genetic testing of BRCA1/2 and other genes (CHEK2, HOXB13, PALB2), including Lynch syndrome genes (MLH1, MSH2, MSH6, and PMS2) in men with metastatic prostate cancer. The potential impact of genetic testing on systemic treatments and the significance of the pathogenic results for at-risk family members is discussed.

Quality-of-life implications of risk-reducing cancer surgery.

Modern advances in genetic sequencing techniques have allowed for increased availability of genetic testing for hereditary cancer syndromes. Consequently, more people are being identified as mutation carriers and becoming aware of their increased risk of malignancy. Testing is commonplace for many inheritable cancer syndromes, and with that comes the knowledge of being a gene carrier for some patients. With increased risk of malignancy, many guidelines recommend that gene carriers partake in risk reduction strategies, including risk-reducing surgery for some syndromes. This review explores the quality-of-life consequences of genetic testing and risk-reducing surgery. A narrative review of PubMed/MEDLINE was performed, focusing on the health-related quality-of-life implications of surgery for hereditary breast and ovarian cancer, familial adenomatous polyposis and hereditary diffuse gastric cancer. Risk-reducing surgery almost uniformly decreases cancer anxiety and affects patients' quality of life. Although the overwhelming quality-of-life implications of surgery are neutral to positive, risk-reducing surgery is irreversible and can be associated with short- and long-term side-effects.

Utilization of Genetic Testing Prior to Subspecialist Referral for Cerebellar Ataxia

To evaluate the utilization of laboratory testing in the diagnosis of cerebellar ataxia, including the completeness of initial standard testing for acquired causes, the early use of genetic testing, and associated clinical and nonclinical factors, among a cohort referred for subspecialty consultation. Data were abstracted from records of 95 consecutive ataxia patients referred to one neurogenetics subspecialist from 2006-2010 and linked to publicly available data on characteristics of referral clinicians. Multivariable logistic and linear regression models were used to analyze unique associations of clinical and nonclinical factors with laboratory investigation of acquired causes and with early genetic testing prior to referral. At referral, 27 of 95 patients lacked evidence of any of 14 laboratory studies suggested for initial work-up of an acquired cause for ataxia (average number of tests=4.5). In contrast, 92% of patients had undergone brain magnetic resonance imaging prior to referral. Overall, 41.1% (n=39) had genetic testing prior to referral; there was no association between family history of ataxia and obtaining genetic testing prior to referral (p=0.39). The level of early genetic testing was 31.6%, primarily due to genetic testing despite an incomplete laboratory evaluation for acquired causes and no family history. A positive family history was consistently associated with less extensive laboratory testing (p=0.004), and referral by a neurologist was associated with higher levels of early genetic testing. Among consecutive referrals to a single center, a substantial proportion of sporadic cases had genetic testing without evidence of a work-up for acquired causes. Better strategies to guide decision making and subspecialty referrals in rare neurologic disorders are needed, given the cost and consequences of genetic testing.

Direct to consumer genetic testing: insights from an internet scan

A survey of 38 internet platforms of companies offering genetic testing services direct to consumers was carried out in summer 2008. The internet survey supported the notion held by many experts and discussed by policy advisory bodies that (1) many direct-to-consumer genetic testing (DCGT) offers do not meet a minimum set of quality criteria that can be regarded to be necessary for ensuring adequate information and protection of customers against misleading interpretation of the need for as well as the possible consequences of genetic testing; (2) most DCGT offers fail to provide proper information on the scientific evidence behind genetic testing services offered to customers (clinical validity and utility); (3) many of the companies offering genetic testing services via the internet do not include genetic counseling at all in their services. Only a few urge customers to involve an expert before purchasing a gene test, and “counseling” in most cases only is provided as written information via mail or via web-log.

Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?

Background153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or...

Broad Clinical Spectrum in Silver-Russell Syndrome and Consequences for Genetic Testing in Growth Retardation

Silver-Russell syndrome is a heterogenous disorder characterized by severe intrauterine growth restriction, lack of catch-up after birth, and specific dysmorphisms. In approximately 10% of patients, maternal uniparental disomy of chromosome 7 is detectable, but hypomethylation of the imprinting in 11p15 is the major epigenetic disturbance in Silver-Russell syndrome. The use of strict clinical criteria, indeed, results in relatively high detection rates for the 11p15 epimutation, but we feel that the application of a strict clinical scoring system is not useful in clinical workaday life because of the broad clinical spectrum in 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers. We report on our experience of molecular testing in 188 patients referred for routine diagnostics of Silver-Russell syndrome and in a group of 20 patients with isolated intrauterine growth restriction/postnatal growth retardation. The molecular genetic results in both groups of data showed that 11p15 epimutation and maternal uniparental disomy of chromosome 7 carriers did not always show the unambiguous Silver-Russell syndrome phenotype. In addition to patients with the classical Silver-Russell syndrome phenotype fulfilling the Silver-Russell syndrome-specific scores, genetic testing for the 11p15 epimutation and/or maternal uniparental disomy of chromosome 7 should also be considered in case of "Silver-Russell syndrome-like" phenotypes, for example, mild intrauterine growth restriction and postnatal growth retardation associated with a prominent forehead and triangular face or asymmetry as the only clinical signs. In particular, the lack of intrauterine growth restriction in patients with a Silver-Russell syndrome-like phenotype should not automatically result in exclusion from molecular testing.

In the Family

In the Family Written and directed by Joanna Rudnick PBS, USA, 2008, English, 83 min In the Family first screened on US television network PBS on October 1, 2008. To purchase this film, or for more information, visit http://www.pbs.org/pov/pov2008/inthefamily/index.html For more on the consequences of genetic testing see Lancet Oncol 2008; 9: 1113 In the Family Written and directed by Joanna Rudnick PBS, USA, 2008, English, 83 min In the Family first screened on US television network PBS on October 1, 2008. To purchase this film, or for more information, visit http://www.pbs.org/pov/pov2008/inthefamily/index.html For more on the consequences of genetic testing see Lancet Oncol 2008; 9: 1113

Novel length variant of the polypyrimidine tract within the splice acceptor site in intron 8 of the CFTR gene: consequences for genetic testing using standard assays

Novel length variant of the polypyrimidine tract within the splice acceptor site in intron 8 of the CFTR gene: consequences for genetic testing using standard assays

Assessment of a Decision Aid to Assist Genetic Testing Research Participants in the Informed Consent Process

Limited attention has been given to applying decision-making theories from psychology to the content and process of informed consent in genetic testing research. Data are presented from a study that developed and assessed a psychological theory-based decision aid as part of the informed consent process. This innovative approach assisted at-risk women in assessing the consequences of participating in a research project that offered them free hemophilia A genetic carrier testing. Results suggest: (1) the decision aid can be incorporated into the consent process with few problems; (2) women of varying educational backgrounds can complete the decision aid; (3) while women consider many consequences of genetic testing, their primary focus is on the implications for their family; and (4) this is in marked contrast to the typical benefit-harm statements prepared by researchers for genetic testing.

Ethical issues in the diagnostic genetic testing process

The diagnostic genetic testing process has certain unique ethical features and deserves special consideration. The purpose of this study was to determine through empirical research, using focussed interview, what ethical issues are involved in the diagnostic genetic testing process. This article describes views and perceptions of adult patients, parents of child patients and various personnel groups (n = 30). The ethical issues were analysed classified into three main categories: a) personnel characteristics, including personality, professional skills, morals and values; b) realization of ethical principles in the examination process, with subcategories of knowledge, autonomy, data protection and equity; and c) consequences of genetic testing, including patients' control over their own lives, manifestation of heterogeneity and outlook on the world. Problematic ethical issues in all three main categories were described in a more many‐sided way by parents and personnel than by adult patients. In the future, attention should be paid to the content areas highlighted by the study, in both clinical practice and further studies.

FMR1 gene deletion/reversion: a pitfall of fragile X carrier testing.

The Fragile X syndrome is, in the majority of cases, caused by CGG trinucleotide amplification within the FMR1 gene. The syndrome is rarely caused by point mutations or deletions. Here we describe a family with 2 sons and 1 daughter affected by Fragile X syndrome and 2 unaffected daughters whose carrier status was unknown prior to this study. Analysis of DNA from each of the 2 daughters revealed two alleles in the normal size range. However, 1 daughter carried one allele of 10 CGG repeats that was not present in either the mother or the father. No evidence for mosaicism could be detected. Haplotype analysis of flanking polymorphic markers revealed that the 10 CGG allele was derived from the mutated allele inherited from the mother. Thus, this case most likely represents an additional case of a reverse mutation from a premutation allele in a female to a normal-sized allele in the offspring. It remains unclear how frequently such reversion events occur. The observation has important consequences for genetic testing, because many laboratories prescreen for the Fragile X syndrome by determining the length of the CGG repeat using PCR. If this shows alleles in the normal size range, a diagnosis of Fragile X syndrome is considered to be excluded. Because the routine PCR and/or Southern blot analyses alone may yield false-negative results in cases of a regression of the number of CGG repeats, we strongly recommend the inclusion of fragment length or haplotype analysis when determining the carrier status within Fragile X syndrome families.

Psychological effect of genetic testing for Huntington's disease: an update of the literature.

Genetic testing has been available for Huntington's disease for longer than any other adult-onset genetic disorder. The discovery of the genetic mutation causing Huntington's disease allowed the use of predictive testing to identify currently unaffected carriers. Concerns have been raised that predictive testing may lead to an increase in deaths by suicide among identified carriers, and these concerns prompted research to assess the psychological effect of predictive testing for Huntington's disease. This article provides an overview of the literature and draws implications for clinical practice. About 10% to 20% of people at risk for the disease request testing when approached by registries or testing centers. Most available evidence suggests that noncarriers and carriers differ significantly in terms of short-term, but not long-term, general psychological distress. Adjustment to results depended more on psychological adjustment before testing than the testing result itself. Although risk factors for psychological sequelae have been identified, few adverse events have been described, and no obvious contraindications for testing people at risk have been identified. The psychological effects of testing may depend on whether testing was based on linkage analysis or mutation detection. Cohorts enrolled in mutation detection programs have higher levels of depression before and after testing than people who sought genetic testing when linkage analysis was available. Some evidence shows that people who choose to be tested are psychologically selected for a favorable response to testing. The effect of testing on people in settings where less intensive counseling protocols and eligibility criteria are used is unknown. Therefore, genetic testing is best offered as part of comprehensive specialist counseling. The frequency of Huntington's disease in populations of European descent is between 3 and 7 affected people per 100,000 population.1 The mean age of onset of Huntington's disease is 40 years, with a mean duration of 15 years. About 98% of patients with Huntington's disease have an expansion of a trinucleotide (CAG) repeat on the Huntington gene. No medical treatments to delay the onset of disease or prophylactic strategies are available. The discovery of a genetic marker for Huntington's disease in 1983 allowed the use of linkage analysis to identify currently unaffected carriers with a sensitivity of about 96% to 99%.2 Linkage analysis takes advantage of the spatial proximity of a marker and a mutation and requires blood specimens from both affected and unaffected family members from several generations. The nature of linkage analysis is probabilistic, because genetic recombination can occur between markers and the gene during meiosis. Most carriers and noncarriers were given risk estimates of 90% or more and 10% or less, respectively, reflecting the relatively low accuracy of these earlier linkage studies. Since identification of the responsible gene mutation in 1993,3 direct mutation detection methods have been applied, leading to highly accurate predictive testing with a sensitivity and specificity of virtually 100%. Compared with other dominantly inherited genetic traits leading to adult-onset disorders, predictive testing for Huntington's disease has been offered for the longest time.4 Carriers will develop the disease—that is, Huntington's disease confers 100% penetrance, which refers to the proportion of carriers of a genetic alteration who will manifest the effects of it and is equivalent to lifetime incidence. Noncarriers definitely will not develop the disease. When linkage analysis first became available, concerns were raised over the possibility of predictive testing leading to an increase in deaths by suicide among identified carriers. Suicide is well recognized as a serious consequence of Huntington's disease. Results from a carefully designed study showed a 4-fold increase in the suicide rate among people affected compared with the rate of the general white population in the United States.5 Attitudinal surveys of people at risk suggest that between 11% and 33% of participants considered suicide a possible response in the future.6 These data highlighted the need for research to identify predictors of depression and suicidal intention in people entering predictive testing programs for Huntington's disease. The identification of the genetic marker prompted investigation of attitudes to, and the psychological impact of, testing for the disease.