Genetic testing in early-onset atrial fibrillation.

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

Province-Wide Ascertainment of Lynch Syndrome in Manitoba.

BACKGROUND & AIMS: We describe the experience of Lynch syndrome (LS) diagnosis in the province of Manitoba, Canada, over the past 20 years. METHODS: We performed a retrospective review of charts from the provincial Genetics Clinic from January 1, 2000, to May 31, 2023. We extracted data on individuals identified to carry a germline pathogenic or likely pathogenic LS gene variant, the mode of ascertainment, family history, and cascade genetic testing (CGT). Data were stratified and compared before and after the year of implementation (October 2013) of the provincial LS screening program (LSSP) and ascertainment by the LSSP vs clinic referrals (CRs). RESULTS: Between 2014 and 2021, 50 of 101 (49.5%) index cases were identified by the LSSP compared with 51 of 101 (50.5%) from CRs. The proportion of PMS2 variants was 34% (17 of 50) for LSSP index cases compared with 21.6% (11 of 51) for CRs from 2014 to 2021 (P < .001). Among CRs from 2014 to 2021, 24 of 51 (47.1%) families met the Amsterdam criteria, compared with 11 of 50 (22.0%) for the LSSP (P = .01). CGT occurred among 46.8% (95 of 203; average, 1.9 relatives/index) of first-degree relatives of CR index cases vs 36.5% (84 of 230; average, 1.7 relatives/index) of first-degree relatives of LSSP index cases (P = .03). Daughters were most likely to undergo CGT. CONCLUSIONS: A tumor screening program is more effective at detecting individuals with lower penetrant gene variants and families who do not meet traditional family history-based criteria. Cascade genetic testing is higher among clinic referrals compared with the screening program. These findings suggest a complementary role of these 2 ascertainment methods for Lynch syndrome.

Tips for Testing Adults With Suspected Genetic Kidney Disease.

Genetic kidney disease is common but often unrecognized. It accounts for most cystic kidney diseases and tubulopathies, many forms of congenital abnormalities of the kidney and urinary tract (CAKUT), and some glomerulopathies. Genetic kidney disease is typically suspected where the disease usually has a genetic basis or there is another affected family member, a young age at onset, or extrarenal involvement, but there are also many exceptions to these "rules". Genetic testing requires the patient's written informed consent. When a patient declines testing, another later conversation may be worthwhile. Genetic testing not only indicates the diagnosis but also the inheritance pattern, likely at-risk family members, disease in other organs, clinical course, and possibly effective treatments. Sometimes genetic testing does not identify a pathogenic variant even where other evidence is strong. A variant of uncertain significance (VUS) may be reported but should not be used for clinical decision making. It may be reclassified after more information becomes available without necessarily retesting the patient. Patients should be provided with a copy of their genetic test report, the results explained, and at-risk family members offered "cascade" testing. A referral to a clinical geneticist or genetic counselor helps identify affected family members and in providing advice to assist with reproductive decisions.

The cost-effectiveness of germline BRCA testing in metastatic prostate cancer followed by cascade testing of first-degree relatives of mutation carriers.

OBJECTIVES: Metastatic prostate cancer (mPCa) patients with BRCA mutations benefit from targeted treatments (e.g., olaparib). Additionally, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa, however, the value for money of testing mPCa patients and cascade testing of blood-related family members has not been assessed. In this context we evaluated the cost-effectiveness of germline BRCA testing in mPCa patients followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. METHODS: We conducted a cost-utility analysis of germline BRCA testing using two scenarios: 1) testing mPCa patients only; 2) testing mPCa patients and first-degree relatives (FDRs) of those who test positive. A semi-Markov multi-health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. RESULTS: Compared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3,731 and a gain of 0.014 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of AU$265,942/QALY. Extending testing to FDRs of variant positive patients resulted in an ICER of AU$16,392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75,000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. CONCLUSION: BRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers.

Investigating genetic counselors' communication with Lynch syndrome patients about cascade testing: Barriers, facilitators, and strategies.

Cascade testing is an imperative process to engage Lynch syndrome patients' at-risk relatives in early cancer risk reduction interventions. How genetic counselors communicate about cascade testing is crucial to patients' intentions of and actual involvement in family communication. Based on data from 20 interviews with genetic counselors, this qualitative study examined their perceptions of barriers and facilitators of offering cascade testing to at-risk relatives and the specific communication strategies they use to discuss cascade testing with patients. We identified patient-level, genetic counselor-level, and system-level barriers and facilitators of having discussions with Lynch syndrome patients about cascade testing. The qualitative data also revealed four prominent communication strategies that genetic counselors use for such discussions: build rapport, reframe the benefits of family communication, adapt communication, and provide various resources. These findings highlight genetic counselors' needs of practical and structural support to facilitate their communication about cascade testing, especially when patients are hesitant or lack resources or skills to notify at-risk relatives about cascade testing.

Family health beliefs and cascade genetic testing in Asian families with hereditary cancer risk: "Okay, now what?"

The limited literature on Asian family communication of hereditary cancer risk and cascade genetic testing for pathogenic variants (PVs) in BRCA1 and BRCA2 has reported that Asian patients have selective communication of test results and lower cascade testing rates. To better understand the factors that impact communication and cascade testing in Asian families, we conducted an in-depth qualitative study guided by the Health Belief Model. Participants with heterozygous PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2, who identified their family's origins to an Asian country, were recruited from the Stanford Cancer Genetics Research Database in October-November 2021. Utilizing a constructivist approach, we conducted sixteen semi-structured interviews around family communication and cascade genetic testing. The research team analyzed the transcript data using a reflexive thematic approach. Extensive discussions between the research team resulted in three primary themes presented in this paper: (1) the role of family health beliefs in cascade genetic testing, (2) changes in communication as a result of genetic testing, and (3) genetics providers' role in supporting family discussions on cascade genetic testing. Certain health beliefs, such as perceived susceptibility to cancer and self-efficacy to take action, were co-created by family members and these shared beliefs influenced decisions about genetic testing, family communication, and family support during the cascade genetic testing process. Participants shared strategies for how genetics providers can prepare Asian patients for more effective conversations with relatives and better address potential testing barriers by tailoring information and providing anticipatory guidance. This study represents an important contribution to the literature about cascade testing among an underrepresented group. Shared family health beliefs about genetic testing may be particularly relevant for this community and these findings can inform strategies to increase cascade genetic testing in Asian families.

Familial communication and cascade testing following elective genomic testing.

Familial communication of results and cascade genetic testing (CGT) can extend the benefits of genetic screening beyond the patient to their at-risk relatives. While an increasing number of health systems are offering genetic screening as an elective clinical service, data are limited about how often results are shared and how often results lead to CGT. From 2018 to 2022, the Sanford Health system offered the Sanford Chip, an elective genomic test that included screening for medically actionable predispositions for disease recommended by the American College of Medical Genetics and Genomics for secondary findings disclosure, to its adult primary care patients. We analyzed patient-reported data about familial sharing of results and CGT among patients who received Sanford Chip results at least 1 year previously. Among the patients identified with medically actionable predispositions, 94.6% (53/56) reported disclosing their result to at least one family member, compared with 46.7% (423/906) of patients with uninformative findings (p < 0.001). Of the patients with actionable predispositions, 52.2% (12/23) with a monogenic disease risk and 12.1% (4/33) with a carrier status reported that their relatives underwent CGT. Results suggest that while the identification of monogenic risk during elective genomic testing motivates CGT in many at-risk relatives, there remain untested at-risk relatives who may benefit from future CGT. Findings identify an area that may benefit from increased genetic counseling and the development of tools and resources to encourage CGT for family members.

Informational needs of individuals from families harboring BRCA pathogenic variants: A systematic review and content analysis.

PURPOSE: Personalized information is paramount to patient-centered communication and decision-making regarding risk management in hereditary cancer syndromes. This systematic review identified information needs of individuals from families harboring BRCA pathogenic variants and compared findings based on gender (women vs men) and clinical characteristics (patients with cancer vs previvors and BRCA heterozygotes vs untested relatives). METHODS: We screened 8115 studies identified from databases and citation searching. The quality of selected studies was assessed using the Mixed Methods Appraisal Tool. Narrative synthesis was conducted based on content analysis. RESULTS: From 18 selected studies including 1063 individuals, we identified 9 categories of information needs. Risk of bias in the selected studies was moderate. Men, untested relatives, and racial and ethnic minorities were underrepresented. Frequently required information was personalized cancer risk and risk-reducing strategies, including decision-making, family implications of hereditary cancers, psychological issues, and cascade testing. Subgroup analyses showed that information needs depended on gender, personal cancer history, and cascade testing in relatives. CONCLUSION: We identified comprehensive and detailed informational needs of individuals from families harboring BRCA pathogenic variants and gaps in international guidelines. Needs for personalized information varied based on gender, health, and genetic testing status. Findings of this study have implications for genetic counseling, tailoring educational materials, and personalizing interventions.

Cascade testing after exome sequencing: Retrospective analysis of linked family data at 2 US laboratories.

PURPOSE: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications. METHODS: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and relatives categorized on the basis of cascade testing completion. RESULTS: Among the 3723 positive ES results across both laboratories, 426 relatives of 282 probands completed cascade testing (uptake = 7.6%). An average of 1.5 relatives (SD = 0.9) were tested per proband. Of the 426 relatives tested, 200 had a variant of interest detected (variant detection yield = 47.0%). CONCLUSION: In our real-world data analysis, a small proportion of probands with a positive ES result subsequently had relatives complete cascade testing at the same laboratory. However, approximately half of the tested relatives received a clinically significant result that could have implications for clinical management or reproductive planning. Additional research on ways to increase cascade testing uptake is warranted.

Most people share genetic test results with relatives even if the findings are normal: Family communication in a diverse population.

PURPOSE: With increasing utilization of genetic testing, sharing genetic information can become part of general family health communication while providing biological relatives with important information about their own genetic risk. Importantly, little is known about motivations for and barriers to family communication of genetic information in historically underserved populations. METHODS: Using mixed methods, we explored patient experiences with family communication in a study population of English- and Spanish-speaking adults aged 18 to 49 years, enriched for participants from historically underserved backgrounds. Risk screening for hereditary cancer guided genetic testing for cancer risk genes and other medically actionable findings. RESULTS: Most participants overall (91%), including most with normal findings (89%), shared or planned to share their results with relatives. Common motivations for sharing results were to give relatives information about their genetic risk and because the participant thought the results were interesting. Reasons for not sharing were limited contact with relatives, perceptions of limited clinical utility for relatives, and concern that discussion of genetic information was stigmatized or taboo. CONCLUSION: Results demonstrate high rates of sharing genetic information, indicate motivations for sharing go beyond facilitating genetic testing for relatives, and suggest general willingness to share genetic information as part of family health communication.

Racial disparities in cascade testing for cancer predisposition genes.

We sought to determine whether there are racial disparities in cascade testing rates and whether providing testing at no-charge impacts rates in Black and White at-risk-relatives (ARR). Probands with a pathogenic/likely pathogenic germline variant in a cancer predisposition gene were identified up to one year before and up to one year after cascade testing became no-charge in 2017. Cascade testing rates were measured as the proportion of probands who had at least one ARR obtain genetic testing through one commercial laboratory. Rates were compared between self-reported Black and White probands using logistic regression. Interaction between race and cost (pre/post policy) was tested. Significantly fewer Black probands than White probands had at least one ARR undergo cascade genetic testing (11.9% versus 21.7%, OR 0.49, 95% CI 0.39-0.61, p < 0.0001). This was seen both before (OR 0.38, 95% CI 0.24-0.61, p < 0.001) and after (OR 0.53, 95% CI 0.41-0.68, p < 0.001) the no-charge testing policy. Rates of an ARR undergoing cascade testing were low overall, and significantly lower in Black versus White probands. The magnitude of difference in cascade testing rates between Blacks and Whites did not significantly change with no-charge testing. Barriers to cascade testing in all populations should be explored in order to maximize the benefits of genetic testing for both treatment and prevention of cancer.

Optimizing communication strategies and designing a comprehensive program to facilitate cascade testing for familial hypercholesterolemia.

BACKGROUND: This project aimed to optimize communication strategies to support family communication about familial hypercholesterolemia (FH) and improve cascade testing uptake among at-risk relatives. Individuals and families with FH provided feedback on multiple strategies including: a family letter, digital tools, and direct contact. METHODS: Feedback from participants was collected via dyadic interviews (n = 11) and surveys (n = 98) on communication strategies and their proposed implementation to improve cascade testing uptake. We conducted a thematic analysis to identify how to optimize each strategy. We categorized optimizations and their implementation within the project's healthcare system using a Traffic Light approach. RESULTS: Thematic analysis resulted in four distinct suggested optimizations for each communication strategy and seven suggested optimizations that were suitable across all strategies. Four suggestions for developing a comprehensive cascade testing program, which would offer all optimized communication strategies also emerged. All optimized suggestions coded green (n = 21) were incorporated. Suggestions coded yellow (n = 12) were partially incorporated. Only two suggestions were coded red and could not be incorporated. CONCLUSIONS: This project demonstrates how to collect and analyze stakeholder feedback for program design. We identified feasible suggested optimizations, resulting in communication strategies that are patient-informed and patient-centered. Optimized strategies were implemented in a comprehensive cascade testing program.

Electronic medical record documentation of germline genetic evaluations in patients with ovarian cancer.

Germline genetic evaluation is indicated for all patients with epithelial ovarian cancer (EOC). For testing to have clinical utility, results must be documented within the electronic medical record (EMR) and accessible to providers at the point of care, which can be challenging in the context of current EMR limitations and genetic testing processes. We examined the receipt of genetics services and EMR capture of genetic testing results in patients with EOC. We conducted a retrospective chart review to examine germline genetic evaluations among patients with EOC seen by a gynecologic or medical oncologist at the University of Pennsylvania in 2016. EMRs were reviewed to determine: (1) if patients were referred for genetic evaluation; (2) if genetic testing was performed; (3) if results were documented in office notes, scanned third-party test reports, and/or the EMR problem list; (4) if provider notes correctly listed the variant classification. Overall, 413 (62%) of patients had documented genetic testing. Genetic testing was documented in almost all provider notes (96%) and the majority of scanned EMR reports (64%). Pathogenic variants were found in 119 (29%) individuals; the majority (70%) had genetic testing documented within EMR problem lists. Provider notes were highly accurate in describing variant classification. In this study, genetic testing was performed and documented in the EMR for most EOC patients. Approximately one-third of those tested did not have scanned test reports specifying variant found, limiting the utility of test results for cascade testing and therapeutic decisions.

BRCAShare-Assessment of an animated digital message for intrafamilial communication of pathogenic variant positive test results: A feasibility study.

While genetic testing for hereditary breast and ovarian cancer syndrome (HBOC) is well-established in the field of medicine, family members' uptake of cascade genetic testing for known familial pathogenic variants remains low. Probands often become responsible for initiating familial communication about their testing results, and barriers to communication may include difficulty in conveying information to relatives and a lack of communication resources for probands' use. In this study, we tested a two-minute animated digital message (ADM) intervention guided by the Health Belief Model (HBM) in an unselected sample to determine hypothetical individual perceptions of susceptibility and severity and behavioral intention to act on the information provided in the ADM. We recruited genetic testing naïve adults from the United States with no personal history of cancer through Amazon Mechanical Turk to participate in this study. Participants were presented a hypothetical scenario describing a relative's recent HBOC diagnosis, viewed the ADM, and answered a questionnaire assessing participants' perception of the HBM constructs in relation to the hypothetical scenario and participants' intentions to pursue cascade genetic testing, talk to a healthcare professional, or talk to family members after ADM viewing. Participants (n = 373) largely perceived HBOC as serious and believed that they could benefit from the information provided by genetic testing; 76% hypothetically intended to pursue genetic testing at a cost of $100 or less, and 90% intended to either pursue testing or talk to a healthcare provider or family members. This feasibility study in an unaffected population could mimic the experience of distant/less-engaged relatives in HBOC families after receiving unexpected information about cascade genetic testing. Most participants demonstrated behavioral intention toward cascade testing, at a rate higher than literature would suggest is typical in high-risk families, indicating that a theory-supported, simple to use intervention may be useful in clinical practice.

Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.

Germline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer- and polyposis-focused panels, as well as on broader pan-cancer panels. With up to 1%-2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross-sectional self-report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

Impact of BRCA1/2 cascade testing on anxiety, depression, and cancer worry levels among unaffected relatives in a multiethnic Asian cohort.

Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies.

Implementation of a dedicated cascade testing clinic for patients at risk for hereditary cancer syndromes.

Cascade testing, the site-specific genetic testing of relatives within families with an inherited condition, is underutilized. Long wait times for appointments in specialty genetics clinics are a known barrier to genetic testing access. In our cancer genetics, New Patient Clinic (NPC), the long wait time for an appointment (on average 5 months for routine referrals), was identified by both providers and patients as a barrier to uptake of cascade testing. Timely testing of at-risk relatives is essential to maximize the benefits of cascade testing and reduce cancer morbidity and mortality. Our objective was to improve access via implementation of a different clinical model that designated appointments for patients seeking cascade testing. A secondary goal was to improve use of genetic counselor time. We implemented a dedicated Cascade Testing Clinic (CTC) with an expedited triaging and unique scheduling model to decrease patient wait time to appointment and optimize clinician time. We report on the process and outcomes here. Between October 2016 and February 2020, the average wait time between referral date and first scheduled appointment date was 46 days for the CTC compared to 144 days for the NPC (p < 0.0001). No-show/cancelation/rescheduling rate was 11.7% in the CTC compared to 29.7% in the NPC (p < 0.0001). Genetic counselors saw approximately twice as many patients per half-day clinic in the CTC compared to the NPC (p < 0.00001). Modifications to clinic staffing and appointment times were made based on provider feedback. Implementation of a dedicated clinic specifically for patients seeking cascade testing significantly shortened wait times for this population, reduced patient drop-off, and improved clinician efficiency. The relatively straightforward indications and generally uncomplicated medical histories made this an ideal population for expedited appointments.

What happens in the long term: Uptake of cancer surveillance and prevention strategies among at-risk relatives with pathogenic variants detected via cascade testing.

BACKGROUND: Cascade genetic testing for hereditary cancer syndromes offers affected relatives the opportunity to pursue cancer screening and risk-reducing surgery and thus reduces morbidity and mortality. The purpose of this study was to measure the long-term utilization of targeted cancer prevention and quality of life among at-risk relatives offered clinician-facilitated cascade genetic testing. METHODS: In a pilot study, at-risk relatives of patients with a hereditary cancer syndrome were contacted directly by the clinical team and offered telephone genetic counseling and genetic testing via an at-home, mailed saliva kit. Two-year follow-up results evaluating the use of targeted cancer prevention strategies and the quality of life for enrolled relatives were reported. Quality-of-life was measured with validated surveys, and scores were compared to the time of initial contact by the Wilcoxon signed-rank test. RESULTS: Ninety-five at-risk relatives were enrolled in the initial pilot study, and 72 (76%) participated in the 2-year follow-up; 57 of these (79%) had completed genetic testing. Twenty-five of those 57 relatives (44%) were found to harbor an inherited pathogenic variant. Guideline-based cancer surveillance was recommended to 18 relatives; 13 (72%) completed at least one recommended screening, and six (33%) completed all recommended screenings. Risk-reducing surgery was recommended to 10 relatives; four (40%) completed a total of eight procedures. Quality-of-life surveys demonstrated low levels of anxiety, depression, distress, and uncertainty. CONCLUSIONS: The 2-year follow-up of the original pilot study revealed that clinician-facilitated cascade testing resulted in genetically targeted cancer screening and prevention with preserved quality of life. These results, to be confirmed by larger randomized controlled trials, suggest that medical systems should consider supporting clinician-facilitated cascade testing programs.

A pragmatic clinical trial of cascade testing for familial hypercholesterolemia.

PURPOSE: We compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology. METHODS: We enrolled 52 FH probands with a pathogenic variant (FHg+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FHg-). After direct contact by the study team, family members (FMs) of FHg+ probands could opt-in for genetic testing and FMs of FHg- probands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FHg+ families and as low-density lipoprotein cholesterol ≥155 mg/dL in FHg- families. RESULTS: Of 71 FHg+ probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FHg- probands who received counseling, 73 consented and identified 295 FMs (63 consented and were tested, yielding 17 new cases). New case detection per index case was significantly greater in FHg+ than in FHg- families (0.92 vs 0.23), a result of higher cascade testing uptake (43.9 vs 21.4%) and yield (43.2 vs 27.0%) in the former. CONCLUSION: New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

Healthcare Predictors of Information Dissemination About Genetic Risks.

OBJECTIVES: Despite the benefits of genetic counseling and testing (GCT), utilization is particularly low among African American (AA) women who exhibit breast cancer features that are common in BRCA-associated cancer. Underutilization is especially problematic for AA women who are more likely to die from breast cancer than women from any other race or ethnicity. Due to medical mistrust, fear, and stigma that can be associated with genetic services among racial/ethnic minorities, reliance on trusted social networks may be an impactful strategy to increase dissemination of knowledge about hereditary cancer risk. Informed by the social cognitive theory, the purpose of this study is to determine: 1) which AA patients diagnosed with breast cancer and with identified hereditary risk are sharing information about hereditary risk with their networks; 2) the nature of the information dissemination; and 3) if personal GCT experiences is associated with dissemination of information about hereditary risk. METHODS: Among consented participants (n = 100) that completed an interview administered using a 202-item questionnaire consisting of open- and closed-ended questions, 62 patients were identified to be at higher risk for breast cancer. Descriptive statistics, bivariable chi-square, Pearson's exact tests, and regression analyses were conducted to examine differences in characteristics between high-risk participants who disseminated hereditary risk information and participants who did not. RESULTS: Among high-risk participants, 25 (40%) indicated they had disseminated information about hereditary risk to at least one member in their family/friend network and 37 (60%) had not. Receipt of both provider recommendations and receipt of GCT services was associated with greater odds of disseminating information about hereditary risk with networks, OR = 4.53, 95%CI [1.33, 15.50], p = .02. CONCLUSION: Interventions that increase self-efficacy gained through additional personalized knowledge and experience gained through provider recommendations and by undergoing GCT may facilitate information dissemination among social/familial networks.