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UNASSIGNED: Relatives of probands diagnosed with familial hypercholesterolemia (FH) should undergo cascade testing for FH.
UNASSIGNED: The purpose of this study was to evaluate probands\' choices of innovative strategies to communicate their FH result with relatives and facilitate cascade testing uptake.
UNASSIGNED: Probands with an FH genetic result from the MyCode Community Health Initiative could choose to share their FH result with adult blood relatives via the Family and Healthcare Professional Packet (packet), family sharing and cascade chatbots (chatbot), and/or FH Outreach and Support Program (direct contact). Cascade testing uptake was measured as reported completion of genetic or cholesterol testing. Generalized estimating equations models were used to identify factors associated with testing.
UNASSIGNED: One hundred seventy five probands received an FH result, median age was 58.9 (IQR: 44.9-69.3), and 58.9% were female. Probands shared information about 1,915 adult and 163 minor relatives (11.9 relatives per proband). Seventy percent of probands (121/175) selected at least one strategy for at least one adult relative. An average of 1.2 strategies was selected per adult relative. Cascade testing was completed for 26.6% (144/541) of adults with at least one strategy selected, 2.4% (33/1,374) of adults without a strategy selected, and 25.2% (41/163) of minor relatives. Factors associated with increased cascade testing uptake were selection of at least one strategy (6.32 higher odds), specifically, selection of direct contact (16.78 higher odds).
UNASSIGNED: Strategies implemented improved FH cascade testing uptake compared to previous estimates and in families where no strategy was selected. Overall uptake remains insufficient, which can be attributed to probands reluctance to select a strategy for many relatives.

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of -13.0 mg/dL (-61.0, 4.0) versus -1.0 mg/dL (-16.0, 17.0) in probands without GC (p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively (p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing (p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated.

BACKGROUND: When a pathogenic BRCA1 or BRCA2 mutation is identified in a family, cascade genetic testing of family members is recommended since the results may inform screening or treatment decisions in men and women. However, rates of cascade testing are low, and men are considerably less likely than women to pursue cascade testing. To facilitate cascade testing in men, we designed a Web-based genetic education tool that addressed barriers to cascade testing, was individually tailored, delivered proactively, and could be used in lieu of pretest genetic counseling to streamline the cascade testing process.
METHODS: We randomized 63 untested men from hereditary cancer families to Web-based genetic education (WGE) versus enhanced usual care (EUC). WGE participants were provided access to a genetic education website after which they could accept or decline genetic testing or opt for pretest genetic counseling. EUC participants received an informational brochure and a letter informing them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was the uptake of genetic testing.
RESULTS: Men in the WGE group were more likely to complete genetic counseling and/or genetic testing (43% vs. 12.1%; χ2 [n = 63, df = 1] = 7.77, p = 0.005). WGE participants were also more likely to complete genetic testing compared to men in the EUC group (30% vs. 9.1%; χ2 [n = 63, df = 1] = 4.46, p = 0.03).
CONCLUSIONS: This preliminary trial suggests that a streamlined approach to genetic testing using proactively delivered genetic education may reduce barriers to cascade testing for at-risk men, leading to increased uptake. These results should be interpreted cautiously given the select sample and high rate of non-response.

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.

BACKGROUND: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands.
METHODS: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome.
RESULTS: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs.
CONCLUSIONS: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.