Cascade Genetic Testing Research Articles

A CLINICALLY VALIDATED GENETIC SCREENING FOR FAMILIAL HYPERCHOLESTEROLEMIA IN QUÉBEC

<h3>BACKGROUND</h3> Familial Hypercholesterolemia (FH) is the most common genetic disorder in humans with an estimated prevalence of 1/311. In geographic regions with founder effect mutations, such as the province of Québec, prevalence is as high as 1/80. FH is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and therapy of FH can normalize life expectancy, less than 15% of cases are diagnosed. Cascade screening and genetic testing aim to improve diagnosis, treatment, and outcomes in FH. <h3>METHODS AND RESULTS</h3> Here, we report a single center experience with the only clinically validated molecular genetic screening for FH (CLIA compliant) in Canada. We performed next generation sequencing of the LDLR, APOB and PCSK9 genes and multiplex ligation-dependent probe amplification (MLPA) of the LDLR gene to detect genetic mutations and copy number variants. All mutations were reviewed by a geneticist and cross-referenced in ClinVar. Between 2018-2020, we examined 369 FH cases (57% males, 43% females) based on the Canadian FH definition clinical criteria. For index patients, mean age at diagnosis was 40±16 years, while 30±16 years was for cascade screening patients. Baseline (untreated) LDL-C was 6.5±2.0 mmol/L. In 224 patients who underwent genetic testing, a pathogenic mutation was identified in 167 (75%) individuals, in keeping with ∼20% of FH patients with a polygenic form. A majority of affected patients had mutations in the LDLR (87%) or APOB (13%) genes. Interestingly, the genetic panel offered by Québec's Health Ministry, which includes 10 common mutations in French Canadians, only accounted for 46% of identified mutations. Even in patients self-describing as French Canadians, more than 20% did not have a common mutation. We subsequently examined the impact of genetic testing in re-classification of patients' FH diagnosis. There were 3 (1%) individuals with a "severe hypercholesterolemia" phenotype initially categorized as "not FH" and 85 (38%) with "probable FH" re-classified to "definite FH". <h3>CONCLUSION</h3> Genetic testing in patients suspected of having FH provides diagnostic certainty and permits re-classification of individuals with a diagnosis of "severe hypercholesterolemia" or "probable FH" according to current definitions. Furthermore, the limited genetic panel offered by the province of Québec, focusing on common French-Canadian mutations, provides incomplete data in the majority of cases. We therefore propose that most patients with a presumptive diagnosis of FH undergo an unbiased genetic analysis. This study has implications on cascade screening, public health policies and reimbursement of drugs such as PCSK9 inhibitors.

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management.

A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.

Cost-effectiveness of cascade genetic testing for familial hypercholesterolemia in the United States: A simulation analysis

Objective There is no coordinated cascade testing program for familial hypercholesterolemia (FH) in the U.S. We evaluated the contemporary cost-effectiveness of cascade genetic testing relatives of FH probands with a pathogenic variant. MethodsA simulation model was created to simulate multiple family trees starting with progenitor individuals carrying a pathogenic variant for FH who were followed through several generations. This approach allowed us to examine a family tree that had grown sufficiently to have large numbers of relatives across multiple degrees of relatedness. The model estimated costs and life years gained (LYG) when cascade genetic testing was implemented for relatives of FH probands identified through standard care who were at or older than designated age thresholds (5, 10, 15, 20, 25, 30, 35, 40). Costs were valued in 2018 U.S. dollars. Future costs and LYG projected by the model were discounted at an annual rate of 3%. ResultsFor 1st degree relatives, cascade testing at every age threshold resulted in a positive number of average LYG per person, though this number decreased as testing was started at higher age thresholds. Testing was not cost-effective if initiated at an age threshold of 40 and older but was cost-effective at younger age thresholds, with a discounted cost per LYG per person of less than $50,000. For 2nd degree relatives, testing was cost-effective with a screening age threshold of 10 but no longer cost-effective at a threshold of 15 or higher. In more distant relatives, cascade genetic testing was not beneficial or cost-effective. ConclusionsBased on our simulation model, cascade genetic testing for FH in the U.S. is cost-effective if started before age 40 in 1st degree relatives and before age 15 in 2nd degree relatives.

Long-term follow-up of facilitated cascade genetic testing for familial cancer syndromes: do at-risk relatives act on the information gained and what are the quality of life implications?

<h3>Objectives:</h3> In a pilot study, we found that facilitated cascade genetic testing for cancer-associated pathogenic mutations with telephone counseling and mailed saliva kits resulted in testing of 58% of at-risk relatives (ARRs), significantly higher than prior reports. To ascertain the true value of cascade testing, we must determine whether ARRs act upon information gained to prevent cancer morbidity and mortality. We aim to evaluate whether detecting the familial pathogenic mutations in ARRs resulted in utilization of genetically targeted cancer prevention and assess long-term quality of life. <h3>Methods:</h3> ARRs found on cascade genetic testing to harbor a pathogenic mutation were contacted two years following testing for telephone interviews. Interviews focused on utilization of guideline-based cancer preventative medical services, additional testing of family members and quality of life (QOL), assessed via three validated survey instruments (Hospital Anxiety and Depression Scale (HADS), Satisfaction with Decision Scale (SDS) and The Multidimensional Impact of Cancer Risk Assessment Questionnaire (MICRA)). <h3>Results:</h3> Our pilot trial identified 28 ARRs with pathogenic mutations, among which 25 (89%) were contacted successfully for 2-year follow-up. A total of 4 ARRs (19%) had undergone a total of six risk-reducing surgeries as a result of testing results (hysterectomy with salpingo-oophorectomy-3, salpingo-oophorectomy-1, mastectomy-2). A total of 21 ARRs (75%) underwent 35 cancer surveillance interventions (Figure 1). A total of 5 patients (24%) reported that the genetic results affected their fertility planning and three were considering preimplantation genetic diagnosis. A total of 23 patients (92%) reported sharing their genetic testing results with relatives. A total of 12 patients (52%) reported that their testing resulted in additional testing of relatives. ARRs reported that 14 additional relatives underwent testing, 8 were found to carry the familial mutation, 6 of whom underwent cancer surveillance and one underwent risk-reducing surgery. At 2 years following cascade testing, surveys demonstrated low median levels of anxiety (HADS-A 3, IQR 6) and depression (HADS-D 0, IQR 1) and high levels of satisfaction with testing (MICRA 28, IQR 10, SDS 29, IQR 5). <h3>Conclusions:</h3> Long-term follow-up of our pilot study of facilitated cascade testing for cancer-associated pathogenic mutations demonstrates that the majority of ARRs found to carry the familial mutation utilize recommended cancer surveillance interventions and many undergo risk-reducing surgery. Furthermore, we have detected a cascade of the cascade, whereby testing of ARRs leads to iterative rounds of testing of additional relatives who then also have the option for cancer risk reduction. A prospective randomized trial of cascade testing facilitated by the medical team versus standard of care proband-mediated tested is planned and will be critical to shaping the way that the oncology community approaches cascade testing.

Patient ethnicity and cascade genetic testing: a descriptive study of a publicly funded hereditary cancer program.

Cascade genetic testing for hereditary cancer is highly accurate and cost-effective for identifying individuals at high risk for cancer; however, not all eligible people utilize this service. While sociodemographic factors related to the uptake of cascade genetic testing, such as age and sex, have been fairly well described in the literature, there is limited data available regarding patient ethnicity. We analyzed four years of testing data for this factor, as well as sex, age and genes tested. The patients were seen by the Hereditary Cancer Program of BC Cancer, which serves the entire population of British Columbia and Yukon, Canada. Patient ethnicity was compared to the 2016 Census data from the same region. Fisher's exact test was conducted to explore the cascade genetic testing uptakes. Chi-square test was used to compare the major ethnicity groups to Census data. There was significant variability in the uptake of cascade genetic testing in the three largest population groups (p < 0.05), with individuals of European ethnic origin overrepresented, individuals of Asian ethnic origin modestly underrepresented, and individuals of North American Indigenous origin considerably underrepresented for cascade genetic testing. The proportions represented compared to those expected from census data were significantly different for these three largest groups (p < 0.01). The majority of cascade genetic tests were for BRCA1/BRCA2 (58.8%), followed by 16.9% for Lynch syndrome genes. Most patients were female (70%), and the mean age of patients was 49years old. This study provides further insight into uptake of cascade genetic testing by patient ethnicity. Examining patient ethnicity and cascade genetic testing rates helps to identify underserved populations. Our analysis highlights significant underrepresentation of North American Indigenous individuals for hereditary cancer cascade genetic testing, and helps recognize the need for development of culturally-safe alternatives to outreach and service promotion.

Time to Think Differently About Sarcomere-Negative Hypertrophic Cardiomyopathy.

Time to Think Differently About Sarcomere-Negative Hypertrophic Cardiomyopathy.

Uptake of cancer risk management strategies among women who undergo cascade genetic testing for breast cancer susceptibility genes.

Uptake of cancer risk management based on inherited predispositions, which encompasses bilateral mastectomy (BLM), bilateral salpingo-oophorectomy (BSO), and intensified screening, is the primary motivation for cascade testing for hereditary breast and ovarian cancer (HBOC). However, long-term outcome data for cascade testers are lacking. Medical records were abstracted for all unaffected women with pathogenic variants in HBOC genes from 2 cancer hospitals (2013-2019) with at least 1 year of follow-up to compare the uptake of surgery and screening between cascade and noncascade testers. Cascade testers (79.8%) were younger than noncascade testers (mean age, 37.6 vs 43.5 years; P = .002). Among women aged ≥40 years, 43% underwent BLM, and 71.6% underwent BSO, with no significant difference in uptake between cascade and noncascade testers. The mean time to BSO among cascade testers was shorter among women aged ≥40 years versus those aged <40 years (11.8 vs 31.9 months; P = .04); no such difference was observed among noncascade testers. Mammography and breast magnetic resonance imaging rates were low in the recorded 6 years for both groups after genetic counseling. Management uptake among cascade testers is high with rates comparable to those for unaffected BRCA-positive women. A large proportion of women act on cascade test results, and this represents a novel report of utilization of cancer management strategies.

Using a Tailored Digital Health Intervention for Family Communication and Cascade Genetic Testing in Swiss and Korean Families With Hereditary Breast and Ovarian Cancer: Protocol for the DIALOGUE Study.

BackgroundIn hereditary breast and ovarian cancer (HBOC), family communication of genetic test results is essential for cascade genetic screening, that is, identifying and testing blood relatives of known mutation carriers to determine whether they also carry the pathogenic variant, and to propose preventive and clinical management options. However, up to 50% of blood relatives are unaware of relevant genetic information, suggesting that potential benefits of genetic testing are not communicated effectively within family networks. Technology can facilitate communication and genetic education within HBOC families.ObjectiveThe aims of this study are to develop the K-CASCADE (Korean–Cancer Predisposition Cascade Genetic Testing) cohort in Korea by expanding an infrastructure developed by the CASCADE (Cancer Predisposition Cascade Genetic Testing) Consortium in Switzerland; develop a digital health intervention to support the communication of cancer predisposition for Swiss and Korean HBOC families, based on linguistic and cultural adaptation of the Family Gene Toolkit; evaluate its efficacy on primary (family communication of genetic results and cascade testing) and secondary (psychological distress, genetic literacy, active coping, and decision making) outcomes; and explore its translatability using the reach, effectiveness, adoption, implementation, and maintenance framework.MethodsThe digital health intervention will be available in French, German, Italian, Korean, and English and can be accessed via the web, mobile phone, or tablet (ie, device-agnostic). K-CASCADE cohort of Korean HBOC mutation carriers and relatives will be based on the CASCADE infrastructure. Narrative data collected through individual interviews or mini focus groups from 20 to 24 HBOC family members per linguistic region and 6-10 health care providers involved in genetic services will identify the local cultures and context, and inform the content of the tailored messages. The efficacy of the digital health intervention against a comparison website will be assessed in a randomized trial with 104 HBOC mutation carriers (52 in each study arm). The translatability of the digital health intervention will be assessed using survey data collected from HBOC families and health care providers.ResultsFunding was received in October 2019. It is projected that data collection will be completed by January 2023 and results will be published in fall 2023.ConclusionsThis study addresses the continuum of translational research, from developing an international research infrastructure and adapting an existing digital health intervention to testing its efficacy in a randomized controlled trial and exploring its translatability using an established framework. Adapting existing interventions, rather than developing new ones, takes advantage of previous valid experiences without duplicating efforts. Culturally sensitive web-based interventions that enhance family communication and understanding of genetic cancer risk are timely. This collaboration creates a research infrastructure between Switzerland and Korea that can be scaled up to cover other hereditary cancer syndromes.Trial RegistrationClinicalTrials.gov NCT04214210; https://clinicaltrials.gov/ct2/show/NCT04214210 and CRiS KCT0005643; https://cris.nih.go.kr/cris/International Registered Report Identifier (IRRID)PRR1-10.2196/26264

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening.

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.

An actuarial model of arrhythmogenic right ventricular cardiomyopathy and life insurance

Many countries ban insurers from using genetic test results in underwriting. One study [Howard, R. C. W. (2014). Report to CIA research committee: Genetic testing model: If the underwriters had no access to known results. Canadian Institute of Actuaries (CIA).] stated that such a ban in Canada would expose life insurers to adverse selection, causing premiums to increase by 12%. More than a quarter of this cost was attributable to a single disorder, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). We model ARVC in a life insurance market, following the methodology of [Haçarız, O., Kleinow, T. & Macdonald, A. S. (2021). Genetics, insurance and hypertrophic cardiomyopathy. Scandinavian Actuarial Journal 2021, 54–81.], including ‘cascade’ genetic testing (CGT), so the rôle of family history in underwriting is modelled explicitly. We review (in the Appendix) the published epidemiology of ARVC, in particular the existence of an effective treatment, which we also include in our model. Our results are consistent with those of [Macdonald, A. S. & Yu, F. (2011). The impact of genetic information on the insurance industry: Conclusions from the ‘bottom-up’ modelling programme. Astin Bulletin 41(02), 343–376.] and [Haçarız, O., Kleinow, T. & Macdonald, A. S. (2021). Genetics, insurance and hypertrophic cardiomyopathy. Scandinavian Actuarial Journal 2021, 54–81.], namely, that in realistic scenarios premium increases would be negligible. We also consider the possibility of life settlement companies ‘gaming’ insurers by learning of adverse genetic test results, and conclude that to profit from purchasing policies from affected individuals, they would have to predict the future trajectory of the epidemiology of ARVC better than the epidemiologists themselves.

Incorporating Cascade Effects of Genetic Testing in Economic Evaluation: A Scoping Review of Methodological Challenges.

Cascade genetic testing is indicated for family members of individuals testing positive on a genetic test, and is particularly relevant for child health because of their vulnerability and the long-term health and economic implications. Cascade testing has patient- and health system-level implications; however cascade costs and health effects are not routinely considered in economic evaluation. The methodological challenges associated with incorporating cascade effects in economic evaluation require examination. The purpose of this scoping review was to identify published economic evaluations that considered cascade genetic testing. Citation databases were searched for English-language economic evaluations reporting on cascade genetic testing. Nineteen publications were included. In four, genetic testing was used to identify new index patients—cascade effects were also considered; thirteen assessed cascade genetic testing strategies for the identification of at-risk relatives; and two calculated the costs of cascade genetic testing as a secondary objective. Methodological challenges associated with incorporating cascade effects in economic evaluation are related to study design, costing, measurement and valuation of health outcomes, and modeling. As health economic studies may currently be underestimating both the cost and health benefits attributable to genetic technologies through omission of cascade effects, development of methods to address these difficulties is required.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Fully penetrant genetic mutation results in wide familial variability: a cardiac magnetic resonance focused report

Abstract Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by ventricular dilation (LV or biventricular) and systolic dysfunction, with a broad etiological spectrum, comprising numerous genetic and non-genetic causes. Cardiac magnetic resonance (CMR) has become an important tool in guiding the etiological diagnosis in DCM. We present the case of a 37-years old man admitted to our department in order to investigate the diagnosis of DCM using CMR. Cine imaging showed mild left ventricular (LV) dilatation and moderate systolic (LV ejection fraction = 42%) dysfunction, but also apical hypertrabeculation meeting the criteria for non-compaction and late gadolinium enhancement (LGE) images revealed mid-wall fibrosis in the basal and midventricular segments of the inferior interventricular septum (IVS) – typical of non-ischemic DCM. Complete family history revealed the diagnosis of DCM in the mother of the patient and in the maternal grandfather, who had died at 87. After genetic testing of the index patient showed a pathogenic mutation in the TTN (titin) gene (c.79273A&gt;T), cascade genetic testing followed, for his mother, sister, uncle and two cousins who all came back positive for the same mutation. CMR examination of the mother done 6 years prior demonstrated severe LV dilatation and systolic dysfunction (LV ejection fraction = 23%), LV non-compaction and mid-wall IVS fibrosis. CMR examination was performed for the other members of the family and discovered pathological findings in the uncle (normal LV volume and function, but focal mid-wall fibrosis in the inferior IVS) and the male cousin (LV non-compaction), while the female cousin had a normal exam. Using CMR and genetic testing, this case report proves the phenotypic heterogenicity of a completely penetrant titin mutation in the same family. Moreover, CMR is shown to be essential in DCM evaluation, having the ability to guide etiologic diagnosis and to detect alterations such as fibrosis and non-compaction in the absence of LV dilation or dysfunction.

Interventions Facilitating Family Communication of Genetic Testing Results and Cascade Screening in Hereditary Breast/Ovarian Cancer or Lynch Syndrome: A Systematic Review and Meta-Analysis.

Simple SummaryIn general, 5–20% of all cancers are due to pathogenic variants in cancer genes that are passed down in the family. It is recommended that blood relatives of individuals with such a pathogenic variant have genetic testing, to identify if they also carry the same variant. This information will help their healthcare providers to make individualized cancer screening and prevention plans. However, only around 30% of at-risk relatives have genetic testing, presumably due to a lack of communication about inherited cancer genes among family members. In this paper, we identified interventions that were designed to improve family communication about hereditary cancer and/or genetic testing among at-risk relatives for two common hereditary cancer syndromes. We analyzed the components of these interventions and synthesized outcomes with statistical methods. Although we identified 14 eligible studies, there are still many unanswered questions about clinical and research implications with diverse samples to be addressed in future studies.Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results and/or cancer predisposition cascade genetic testing for HBOC and LS. We conducted a systematic review and meta-analysis of randomized trials that assessed intervention efficacy for these two outcomes. Additional outcomes were also recorded and synthesized when possible. Fourteen articles met the inclusion criteria and were included in the narrative synthesis and 13 in the meta-analysis. Lack of participant blinding was the most common risk of bias. Interventions targeted HBOC (n = 5); both HBOC and LS (n = 4); LS (n = 3); or ovarian cancer (n = 2). All protocols (n = 14) included a psychoeducational and/or counseling component. Additional components were decision aids (n = 4), building communication skills (n = 4), or motivational interviewing (n = 1). The overall effect size for family communication was small (g = 0.085) and not significant (p = 0.344), while for cascade testing, it was small (g = 0.169) but significant (p = 0.014). Interventions show promise for improving cancer predisposition cascade genetic testing for HBOC and LS. Future studies should employ family-based approaches and include racially diverse samples.

Disclosure of familial implications of pathogenic variants in breast-cancer genes to patients: Opportunity for prompting family communication.

Familial communication of pathogenic genetic variants is necessary to maximize the clinical utility of genetic testing and its public health benefits. Insights to family communication considerations may be obtained from existing clinical documentation available in medical records. The goal of this study was to describe and characterize information about family communication of pathogenic variants and cascade genetic testing from genetic counseling summary notes. We completed structured content analysis of 656 summary notes describing pathogenic variants in breast cancer genes, for patients seen at a tertiary cancer center. Patients were 89.5% female, median age of 49 years, 32.6% non-White, and were counseled by 23 unique genetic counselors (GCs) with mean post-certification experience of 3.7 years. Cascade genetic testing was documented in 92.2% of all notes. Specific relatives (i.e., relationship to patient) who would benefit from genetic counseling and cascade testing were referenced in 33.1% of notes. Specific risk messaging was 2.5 times more likely to be present in notes of high- compared to moderate-risk genes (OR=2.53, 95% CI: 1.71-3.80), and when summary notes indicated the presence of a friend or relative (OR=2.29, 95% CI: 1.50-3.48). Summary notes frequently attempted to contextualize the patients' familial relationships by referencing positive family communication patterns (41.6%) or negative communication issues (2.4%) and included various strategies to address barriers to communication and assist relatives with cascade testing. Overall, GCs consistently documented family communication recommendations when pathogenic variants are identified on patients' genetic testing, albeit with heterogeneous use of specific communication prompts.

Role of Clinical Genetic Testing in the Management of Aortopathies.

Thoracic aortic aneurysms (TAA) have a strong heritable basis, and identification of a genetic etiology has important implications for patients with TAA and their relatives. This review provides an overview of Mendelian causes of TAA, discusses important considerations for genetic testing, and summarizes the impact a genetic diagnosis may have on a patient's medical care. Thoracic aortic disease may be non-syndromic or seen as part of a genetic syndrome, such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome. Expanded access to genetic testing has revealed the wide and overlapping phenotypic spectrum of these conditions, highlighting the need for genetic testing to establish an accurate diagnosis. Important aspects of genetic evaluation include thorough phenotyping through family history and physical examination, selection of an appropriate genetic test driven by the patient's phenotype, and careful interpretation of genetic test results. Improved understanding of the natural history of these conditions has led to tailored management recommendations, including gene-based recommendations for prophylactic surgical repair. Identification of a genetic etiology allows for careful monitoring of disease progression, informs the timing of prophylactic surgical repair, and facilitates the identification of other at-risk relatives through cascade genetic testing.

Hypertrophic Cardiomyopathy: Genetic Testing and Risk Stratification.

Our knowledge of the genetic basis and molecular pathogenesis of hypertrophic cardiomyopathy (HCM) continues to evolve. We describe the genetic basis of HCM, recent advances in genetic testing and the role of genetics in guiding risk stratification and management, both now and in the future. While initially thought to be an exclusively Mendelian disease, we now know there are important HCM sub-groups. A proportion will have sarcomere variants as the cause of their disease, while others will have genetic variants in genes that can give rise to conditions that can mimic HCM. The role of genetics is primarily for cascade genetic testing, though there is emerging evidence of a role for prognosis and patient management. Genetic testing is a useful addition to management. Genotype may play a greater role in risk stratification, management, treatment and prognosis in future, offering improved outcomes for patients and their families with HCM.

The impact of a cascade testing video on recipients' knowledge, cognitive message processing, and affective reactions: A formative evaluation.

Cascade genetic testing is essential to clarify cancer risk in families with hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants (PVs) in BRCA1 or BRCA2. To date, data suggest that family communication of genetic testing results, with or without the aid of clinical resources such as a provider-written family letter, is impacted by multiple barriers. These barriers eventually lead to sub-optimal uptake of cascade genetic testing. We designed a 2-min animated video that a proband can share with relatives to notify them that the proband has tested positive for a pathogenic variant in BRCA1 or BRCA2. We studied the video via hypothetical scenario in an unselected population to simulate the process by which a relative receives unsolicited genetics information about their family member. We assessed the impact of the video on three specific domains: knowledge, cognitive message processing, and affective reactions. A total of 399 participants recruited through Amazon Mechanical Turk completed the study, and 373 were analyzed. The video significantly improved content knowledge/recall (p<.0001) from pre- to post-video viewing, indicating effective message communication. Items used to measure cognitive processing showed preliminary tendencies toward systematic message processing, which could be desired in familial communication aimed at initiating a specific action-in this case, cascade genetic testing. A majority of participants (66%) reported positive affective reaction as they indicated that they would feel gratitude if they received the video message from a relative, and did not evidence a negative affective reaction to receiving the information. Our data suggest that a video message can effectively communicate information about cascade genetic testing to potential relatives with as little as two minutes of content. Our data suggest that video messaging to assist family communication is a reasonable approach that increases understanding and is unlikely to cause harm.

Please Wait for the Host to Start This Meeting: A Push for H.R. 3235 Amid COVID-19.

Please Wait for the Host to Start This Meeting: A Push for H.R. 3235 Amid COVID-19.

Distress and anxiety associated with identifying germline cancer-associated mutations with cascade genetic testing

Objective: Cascade genetic testing is essential for identifying inherited cancer-associated mutation in at-risk relatives. However, the new diagnosis of a pathogenic mutation can lead to anxiety and distress, and strategies to mitigate this have not been well studied. We sought to evaluate immediate and long-term distress and anxiety among at-risk relatives found to have a pathogenic mutation on cascade genetic testing.