Genetic Susceptibility Testing Research Articles

Abstract LB232: Implementation of population-based risk assessment for hereditary cancer in primary care: Results from the Early Detection of Genetic Risk (EDGE) Trial

Abstract The EDGE (Early Detection of GEnetic risk) trial compared two population-based engagement strategies for identifying primary care patients with a family or personal history of cancer and offered eligible individuals genetic testing for cancer susceptibility (GT). A total of twelve clinics from two healthcare systems (6 clinics each) participated in Montana, Wyoming and Washington State. Clinics were cluster-randomized to one of two engagement approaches: 1) point of care screening (POC), conducted by clinic staff when a patient came in for their appointment and 2) direct patient engagement (DPE), where letter and email outreach facilitated online home screening. Patients who completed screening and met pre-specified personal and family history criteria were offered GT via a home-delivered saliva kit at no cost. The two primary outcomes of the trial were the fraction of active clinic patients who 1) completed the risk assessment tool and 2) completed GT. Logistic regression models were used to compare POC and DPE, allowing for overdispersion and including clinic as a design factor. Analyses in the screened population were adjusted for age, sex, personal and/or family history of cancer, and healthcare system. Over a 12-month engagement window, 95,623 patients were seen in the 12 clinics (Table 1). The POC approach resulted in a higher proportion screened for hereditary risk (19.1% vs. 8.7%), but a similar proportion completed testing (1.5% vs. 1.6%). Notably, the rate of testing among eligible patients approached via POC was approximately half the rate observed with DPE (24.7% vs. 44.7%). POC screen completers were less likely to have a personal history of cancer (9.1% vs. 10.7%), a significant family history of cancer (9.5% vs. 12.8%), and, if eligible, order a test kit (33.8% vs. 58.1%). Overall, a POC approach resulted in higher screening rates for familial cancer risk but a similar fraction completing GT, with DPE screeners self-selecting due to greater personal and/or family history of cancer. Analyses are ongoing to examine patient, clinic and system-level factors predicting screening and testing uptake, which can inform best practices for population-based hereditary cancer screening efforts. POC % (N) DPE % (N) Unadjusted OR (POC vs DPE) Adjusted OR * (POC vs DPE) p-value Patient Denominator 51,693 43,930 Completed Screening 19.1% (9892) 8.7% (3813) 2.49 - 0.0074 Completed GT 1.5% (757) 1.6% (717) 0.89 - 0.75 Screened Participants 9892 3813 % screened with any personal cancer history 9.1% (902) 10.7% (406) 0.77 <0.0001 % of screened with significant** family history of cancer 9.5% (935) 12.8% (487) - 0.69 <0.0001 % of screened found eligible for GT 31.0% (3070) 42.0% (1603) - 0.65 <0.0001 Participants eligible for GT 3070 1603 % of eligible who ordered test kit 33.8% (1039) 58.1% (932) - 0.43 <0.0001 % of eligible who completed GT 24.7% (757) 44.7% (717) - 0.49 <0.0001 *Adjusted ORs - Adjusted for age, sex, personal cancer history, family cancer history, healthcare system.**Significant family history: 2 or more first degree relatives with a high-risk cancer Citation Format: Elizabeth M. Swisher, Heather M. Harris, Barbara M. Norquist, Jeannine Brant, Brian Shirts, Sarah Knerr, Emerson J. Dusic, Faith Beers, Tesla N. Theoryn, DaLaina Cameron, Howard Cabral, Laurie A. Riemann, Michael Raff, Beth Devine, Deborah J. Bowen, Catharine Wang. Implementation of population-based risk assessment for hereditary cancer in primary care: Results from the Early Detection of Genetic Risk (EDGE) Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB232.

A Case of Multidrug-Resistant Tuberculosis in an Active Duty Military Health Care Worker.

Cases of active tuberculosis (TB) in the U.S. Military have fallen over the last century in large part due to improved screening and treatment options. The subset of multidrug-resistant TB (MDR-TB) is almost nonexistent within the U.S. Military. We present a case of MDR-TB in an active duty U.S. Military health care worker and discuss several considerations for treatment that may present challenges for U.S. Military medical practitioners. A 30-year-old active duty Soldier was referred to Army public health services after a bronchoscopy sample was positive for Mycobacterium tuberculosis complex. Sputum smears were negative for acid-fast bacilli, suggesting lower risk for community spread. One month after initiation of the standard 4-drug regimen for active TB, genetic susceptibility testing found the patient's M. tuberculosis isolate to be resistant to rifampin, isoniazid, and pyrazinamide. Contact investigation efforts among co-workers and family members fortunately found no new interferon-gamma release assay conversions. Coordination of public health assets to ensure a successful treatment regimen occurred across varied local, state, and federal agencies. Atypical medications required coordination with the FDA for procurement. An extensive surveillance plan for medication adverse effects was required. Finally, questions of public health authority versus patient autonomy arose requiring multidisciplinary input and ethical discussions.

Allopurinol hypersensitivity syndrome Raising awareness of an uncommon but potentially serious adverse event among kidney stone patients.

Allopurinol is a commonly prescribed agent in the urologic population for the prevention of urinary stones. Although generally well-tolerated, several serious potential side effects can occur with its use. Allopurinol hypersensitivity syndrome (AHS), in particular, is a relatively rare but potentially life-threatening complication. With the observed increase in urinary stone disease, especially those of uric acid composition, it is likely that the use of allopurinol will increase. Urologists play an important role in the assessment and medical management of patients with urinary stones, thus a greater awareness of the potential adverse events associated with allopurinol use, especially AHS, is important, as well as strategies that can minimize such risks. Herein, we review the potential adverse effects of allopurinol. In addition, the results of a comprehensive review of the current literature on AHS will be presented, highlighting those patients at highest risk, reviewing the genetic susceptibility testing currently available, and providing guidance on best practices when allopurinol therapy is being considered.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study

BackgroundApolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one’s genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment.MethodsAn online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran’s Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios.ResultsMost participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements, e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk.ConclusionsOur findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.

Status and Challenge of Antifungal Stewardship at the Osaka Metropolitan University Hospital.

Antifungal stewardship (AFS), compared with antimicrobial stewardship (AS), requires more advanced knowledge, skills, and multidisciplinary collaboration in its implementation. Therefore, fewer facilities are performing AFS compared with AS. At our hospital, we started AS and AFS in 2014. Our AFS programs include the following: i) interventions for patients with yeast-positive blood cultures, ii) introduction of a conditional antifungal notification system, and iii) commencement of AS team rounds. AFS for filamentous fungi includes bronchoscopy and microbial identification, including genetic and drug susceptibility testing. These AFS activities have improved several processes and outcome measures. However, our AFS team has faced several problems owing to the impact of COVID-19. This review introduces the practice of AFS, which we initiated at our hospital in 2014, and presents the current problems.

National Prevalence of Caprine Prion Protein Genetic Variability at Codons 146, 211, and 222 in Goat Herds in the United States.

Scrapie is a neurodegenerative disease that impacts sheep and goats, characterized by gradual and progressive changes in neurological function. Recent research shows that the scrapie incubation period is significantly influenced by specific variations in amino acids within the prion protein gene (PRNP). The objective of this study was to estimate the national prevalence of caprine PRNP genetic variability at codons 146, 211, and 222 in goat populations across the United States. A total of 3052 blood, ear tissue, and brain tissue samples were collected from goats from 50 states. The participating states were categorized into four Veterinary Service (VS) district regions. The samples underwent DNA extraction, and the PRNP variants corresponding to codons 146, 211, and 222 were amplified and sequenced. The analysis of PRNP variants, when compared to the PRNP reference sequence, revealed seven alleles in twelve genotypes. The homozygous 146NN, 211RR, and 222QQ alleles, which have been linked to an increased risk of scrapie, were found to be the most prevalent among all the goats. The heterozygous 222QK, 211RQ, 146SD, 146ND, and 146NS alleles and the homozygous 222KK, 146SS, and 146DD alleles, known to be associated with reduced scrapie susceptibility and a prolonged incubation period after experimental challenge, were found in 1.098% (222QK), 2.33% (211RQ), 0.58% (146SD), 3.13% (146ND), 20.68% (146NS), 0.005% (222KK), 3.31% (146SS), and 0.67% (146DD) of goats, respectively. The 222QK allele was found most frequently in goats tested from the east (VS District 1, 1.59%) and southwest (VS District 4, 1.08%) regions, whereas the 211RQ allele was found most often in goats tested from the Midwest (VS District 2, 8.03%) and east (VS District 1, 6.53%) regions. The 146NS allele was found most frequently in goats tested from the northwest (VS District 3, 29.02%) and southwest (VS District 4, 20.69%) regions. Our results showed that the prevalence of less susceptible genotypes at PRNP codon 146 may be sufficient to use genetic susceptibility testing in some herds. This may reduce the number of goats removed as part of a herd clean-up plan and may promote the selective breeding goats for less susceptible alleles in high-risk herds at the national level.

Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: A survey study

AbstractBackgroundApolipoprotein‐E (APOE) genetic susceptiblity testing for Alzheimer’s disease (AD) dementia is becoming more important as clinical trials are increasingly targeting individuals carrying APOE4‐genotypes. As little is known about about the interest in knowing genetic risk for AD dementia in the general population. Our objective was to examine this in a sample of cognitively normal adults within a population‐based online research registry with the goal to implement APOEε4 status for trial recruitment.MethodAn online survey was completed by 442 cognitively normal participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia, and the knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOEε4/ε4 genotypes). All hypothetical scenarios were randomly presented to all participants. Cochran’s Q‐tests was used to analyse differences in frequencies across scenarios.ResultThe vast majority of participants was interested in participating in research and disclosure of their genetic risk (81%; Figure 1). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, while lower‐educated participants more often reported to be unsure. When provided with different risk scenario’s, interest in knowing their risk was somewhat higher in the scenario’s with higher risk (50% scenario (79%) and 30% scenario (77%)) than in the 10% scenario (73%; χ2(2) = 19.91;p<.001). Most individuals expected they would share their genetic risk with close relatives (77‐89%), would participate in medication trials (79‐88%), and would make long‐term arrangements, e.g. retirement, health care, will (69‐82%), with larger proportions for scenarios with higher hypothetical genetic risk.ConclusionOur findings indicate that the vast majority of cognitively normal adults participating in a research registry is interested in AD genetic risk research participation and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOEε4 genotypes. This suggests APOEε4 screening within an online research registry is potentially a well‐received method to accelerate inclusion for preclinical trials ultimately disclosing genetic risk.

Co-design of patient information leaflets for germline predisposition to cancer: recommendations for clinical practice from the UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar Programme and the Association of Genetic Nurse Counsellors (AGNC)

BackgroundTesting for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due...

Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program.

Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants. The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated. One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology. Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.

Knowledge of Cancer Genetics and the Importance of Genetic Testing: A Public Health Study.

Background Cancer represents a global concern as the second-leading cause of mortality worldwide. It is defined as a genetic disease that develops as a result of several genetic abnormalities and changes to specific genes. Thus, early preventive measures and clinical interventions can be implemented with impressive results using genetic testing and screening for hereditary susceptibility. Objectives The present study assessedthe knowledge of cancer genetics and of the importance of genetic testing among the general population in Saudi Arabia's Makkah Province. Methods A descriptive cross-sectional study was conducted among the general population in Makkah Province. The data were collected through an online questionnaire from November 2022 through December 2022. Results The study recruited 1,329 participants, the largest group of whom were 21-30 years old (n=524, 39.4%). About 60.1% of the respondents were female. The findings reveal that 52.52% of the respondents had poor knowledge, while only 4.82% exhibited good knowledge. Conclusion Approximately half the total participants possessed an inadequate understanding of cancer genetics and the importance of genetic testing. This indicates the need for awareness campaigns and programs to improve the general population's understanding of the genetic predisposition to cancer.

Genetic Testing for Cancer Susceptibility

Allison W. Kurian, MD, MSc; Paul Abrahamse, MA; Allison Furgal, PhD; Kevin C. Ward, PhD; Ann S. Hamilton, PhD; Rachel Hodan, MS; Rachel Tocco, MS; Lihua Liu, PhD; Jonathan S. Berek, MD, MMSc; Lily Hoang, BS; Amal Yussuf, BS; Lisa Susswein, MS, MHA; Edward D. Esplin, MD, PhD; Thomas P. Slavin, MD; Scarlett L. Gomez, PhD; Timothy P. Hofer, MD; Steven J. Katz, MD, MPH

Patient decision support resources inform decisions about cancer susceptibility genetic testing and risk management: a systematic review of patient impact and experience.

Patients with genetic cancer susceptibility are presented with complex management options involving difficult decisions, for example about genetic testing, treatment, screening and risk-reducing surgery/medications. This review sought to explore the experience of patients using decision support resources in this context, and the impact on decision-making outcomes. Systematic review of quantitative, qualitative and mixed-methods studies involving adults with or without cancer who used a decision support resource pre- or post-genetic test for any cancer susceptibility. To gather a broad view of existing resources and gaps for development, digital or paper-based patient resources were included and not limited to decision aids. Narrative synthesis was used to summarise patient impact and experience. Thirty-six publications describing 27 resources were included. Heterogeneity of resources and outcome measurements highlighted the multiple modes of resource delivery and personal tailoring acceptable to and valued by patients. Impact on cognitive, emotional, and behavioural outcomes was mixed, but mainly positive. Findings suggested clear potential for quality patient-facing resources to be acceptable and useful. Decision support resources about genetic cancer susceptibility are likely useful to support decision-making, but should be co-designed with patients according to evidence-based frameworks. More research is needed to study impact and outcomes, particularly in terms of longer term follow-up to identify whether patients follow through on decisions and whether any increased distress is transient. Innovative, streamlined resources are needed to scale up delivery of genetic cancer susceptibility testing for patients with cancer in mainstream oncology clinics. Tailored patient-facing decision aids should also be made available to patients identified as carriers of a pathogenic gene variant that increases future cancer risks, to complement traditional genetic counselling. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020220460, identifier: CRD42020220460.

Validation of the BOADICEA model for predicting the likelihood of carrying pathogenic variants in eight breast and ovarian cancer susceptibility genes

BOADICEA is a comprehensive risk prediction model for breast and/or ovarian cancer (BC/OC) and for carrying pathogenic variants (PVs) in cancer susceptibility genes. In addition to BRCA1 and BRCA2, BOADICEA version 6 includes PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. To validate its predictions for these genes, we conducted a retrospective study including 2033 individuals counselled at clinical genetics departments in Denmark. All counselees underwent comprehensive genetic testing by next generation sequencing on suspicion of hereditary susceptibility to BC/OC. Likelihoods of PVs were predicted from information about diagnosis, family history and tumour pathology. Calibration was examined using the observed-to-expected ratio (O/E) and discrimination using the area under the receiver operating characteristics curve (AUC). The O/E was 1.11 (95% CI 0.97–1.26) for all genes combined. At sub-categories of predicted likelihood, the model performed well with limited misestimation at the extremes of predicted likelihood. Discrimination was acceptable with an AUC of 0.70 (95% CI 0.66–0.74), although discrimination was better for BRCA1 and BRCA2 than for the other genes in the model. This suggests that BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing for hereditary susceptibility to BC/OC despite suboptimal calibration for individual genes in this population.

Pathogenic variant profile in DNA damage response genes correlates with metastatic breast cancer progression-free survival in a Mexican-mestizo population.

Metastatic breast cancer causes the most breast cancer-related deaths around the world, especially in countries where breast cancer is detected late into its development. Genetic testing for cancer susceptibility started with the BRCA 1 and 2 genes. Still, recent research has shown that variations in other members of the DNA damage response (DDR) are also associated with elevated cancer risk, opening new opportunities for enhanced genetic testing strategies. We sequenced BRCA1/2 and twelve other DDR genes from a Mexican-mestizo population of 40 metastatic breast cancer patients through semiconductor sequencing. Overall, we found 22 variants -9 of them reported for the first time- and a strikingly high proportion of variations in ARID1A. The presence of at least one variant in the ARID1A, BRCA1, BRCA2, or FANCA genes was associated with worse progression-free survival and overall survival in our patient cohort. Our results reflected the unique characteristics of the Mexican-mestizo population as the proportion of variants we found differed from that of other global populations. Based on these findings, we suggest routine screening for variants in ARID1A along with BRCA1/2 in breast cancer patients from the Mexican-mestizo population.

Public perspective on medications to delay Alzheimer's disease symptoms.

Disease-modifying treatments for Alzheimer's disease are emerging. Our research examined how personal risk for AD may influence intentions to ask for medications to delay symptoms of AD, and how the availability of such medications impacts interest in AD-related genetic testing. Invitations to a web-based survey were posted on social media sites. Respondents were sequentially assigned to imagine that they had a 5%, 15%, or 35% chance of developing AD. They were then provided a hypothetical scenario describing a medication that delayed AD symptoms. After reporting intentions to ask for the medication, respondents were asked about their interest in genetic testing to predict AD risk. Data from 310 individuals were analyzed. Intentions to ask for a preventative medication were greater for respondents presented AD risks of 35% compared to risks of 15% and 5% (86% vs. 66% vs. 62%, respectively, p < 0.001). The proportion who would ask for genetic susceptibility testing increased from 58% to 79% when respondents were told to imagine that a medication that delayed AD symptoms existed (p < 0.001). Findings suggest that individuals who know they have an increased risk for AD are more likely pursue medications to delay onset of disease symptoms, and the availability of AD-delaying treatments will increase interest in associated genetic testing. Findings provide insight about who will pursue emerging preventative medications, including individuals for whom the medications may be inappropriate, and the impact on genetic test utilization.

Virotyping and genetic antimicrobial susceptibility testing of porcine ETEC/STEC strains and associated plasmid types.

Enterotoxigenic Escherichia coli (ETEC) infections are the most common cause of secretory diarrhea in suckling and post-weaning piglets. For the latter, Shiga toxin-producing Escherichia coli (STEC) also cause edema disease. This pathogen leads to significant economic losses. ETEC/STEC strains can be distinguished from general E. coli by the presence of different host colonization factors (e.g., F4 and F18 fimbriae) and various toxins (e.g., LT, Stx2e, STa, STb, EAST-1). Increased resistance against a wide variety of antimicrobial drugs, such as paromomycin, trimethoprim, and tetracyclines, has been observed. Nowadays, diagnosing an ETEC/STEC infection requires culture-dependent antimicrobial susceptibility testing (AST) and multiplex PCRs, which are costly and time-consuming. Here, nanopore sequencing was used on 94 field isolates to assess the predictive power, using the meta R package to determine sensitivity and specificity and associated credibility intervals of genotypes associated with virulence and AMR. Genetic markers associated with resistance for amoxicillin (plasmid-encoded TEM genes), cephalosporins (ampC promoter mutations), colistin (mcr genes), aminoglycosides (aac(3) and aph(3) genes), florfenicol (floR), tetracyclines (tet genes), and trimethoprim-sulfa (dfrA genes) could explain most acquired resistance phenotypes. Most of the genes were plasmid-encoded, of which some collocated on a multi-resistance plasmid (12 genes against 4 antimicrobial classes). For fluoroquinolones, AMR was addressed by point mutations within the ParC and GyrA proteins and the qnrS1 gene. In addition, long-read data allowed to study the genetic landscape of virulence- and AMR-carrying plasmids, highlighting a complex interplay of multi-replicon plasmids with varying host ranges. Our results showed promising sensitivity and specificity for the detection of all common virulence factors and most resistance genotypes. The use of the identified genetic hallmarks will contribute to the simultaneous identification, pathotyping, and genetic AST within a single diagnostic test. This will revolutionize future quicker and more cost-efficient (meta)genomics-driven diagnostics in veterinary medicine and contribute to epidemiological studies, monitoring, tailored vaccination, and management.

Psychosocial factors impacting barriers and motivators to cancer genetic testing.

Only a small proportion of patients who qualify for clinical genetic testing for cancer susceptibility get testing. Many patient-level barriers contribute to low uptake. In this study, we examined self-reported patient barriers and motivators for cancer genetic testing. A survey comprised of both new and existing measures related to barriers and motivators to genetic testing was emailed to patients with a diagnosis of cancer at a large academic medical center. Patients who self-reported receiving a genetic test were included in these analyses (n= 376). Responses about emotions following testing as well as barriers and motivators prior to getting testing were examined. Group differences in barriers and motivators by patient demographic characteristics were examined. Being assigned female at birth was associated with increased emotional, insurance, and family concerns as well as increased health benefits compared to patients assigned male at birth. Younger respondents had significantly higher emotional and family concerns compared to older respondents. Recently diagnosed respondents expressed fewer concerns about insurance implications and emotional concerns. Those with a BRCA-related cancer had higher scores on social and interpersonal concerns scale than those with other cancers. Participants with higher depression scores indicated increased emotional, social and interpersonal, and family concerns. Self-reported depression emerged as the most consistent factor influencing report of barriers to genetic testing. By incorporating mental health resources into clinical practice, oncologists may better identify those patients who might need more assistance following through with a referral for genetic testing and the response afterwards.

Disclosure of Genetic Risk Factors for Alzheimer's Disease to Cognitively Healthy Individuals-From Current Practice towards a Personalised Medicine Scenario.

Alzheimer's disease (AD) is a genetically complex disorder. In addition to the relatively small number of pathogenic variants causing autosomal dominant AD, many others have been associated with the much more common sporadic form. The E4 allele of the Apolipoprotein E (APOE) is the first discovered genetic risk factor for AD. In addition, more than 70 genetic risk loci contributing to AD have been identified. Current guidelines do not recommend AD susceptibility genetic testing in cognitively healthy adults because the implications for clinical care are limited. However, secondary prevention clinical trials of disease-modifying therapies enrol individuals based on genetic criteria, and participants are often informed of APOE testing results. Moreover, the availability of direct-to-consumer genetic testing allows individuals to learn their own AD genetic risk profile without medical supervision. A number of research protocols for AD susceptibility genetic testing have been proposed. In Italy, disclosure processes and protocols beyond those developed for inherited dementia have not been established yet. We reviewed the literature on the current practice and clinical issues related to disclosing AD genetic risk to cognitively healthy individuals and provide suggestions that may help to develop specific guidelines at the national level.

Abstract A029: A randomized study of two Strategies of remote Genetic Education, Risk Assessment, and Testing (GENERATE) for family members of patients with pancreatic cancer

Abstract Background: Uptake of genetic testing for cancer susceptibility in family members of cancer patients is suboptimal. The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated two strategies of remote genetic education and testing in relatives of pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Eligible participants had: a first-degree relative with PDAC or had a known pathogenic germline variant (PGV) in one of thirteen PDAC predisposition genes (APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53) and a first- or second-degree relative with PDAC. Participants were cluster-randomized by family into one of two arms. Arm 1 included an interactive telemedicine session with a genetic counselor, followed by genetic testing at a commercial laboratory. Arm 2 involved remote online genetic education and testing at the commercial laboratory without the interactive session. The primary outcome was uptake of genetic testing across study arms, which was compared by permutation tests and mixed-effects logistic regression models. Results: Between 5/8/2019 and 6/1/2021, 424 families were randomized, including 601 participants (n=296 Arm 1; n=305 Arm 2). The uptake of genetic testing was 87% (257/296) in Arm 1 and 93% (284/305) in Arm 2 (p=0.014). Participants in Arm 1 were significantly less likely to obtain genetic testing compared to Arm 2 (Adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). BRCA2, ATM, CDKN2A and PALB2 were the most common PDAC susceptibility genes in which PGVs were identified. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional germline susceptibility testing. Citation Format: Nicolette J. Rodriguez, C. Sloane Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Ileana Fortes, Alyson Caruso, Alison N. Schwartz, Jill E. Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H. Nelson, Sydney Okumura, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Miki Horiguchi, Allyson J. Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. A randomized study of two Strategies of remote Genetic Education, Risk Assessment, and Testing (GENERATE) for family members of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A029.

POST COVID RECURRENT FEVER IN A CHILD WITH GENETIC SUSCEPTIBILITY TO FAMILIAL MEDITERRANEAN FEVER

<h3>Introduction</h3> Children and adults with post-acute sequelae of COVID (PASC) sometimes report recurrent fevers. We present the case of 13-year-old male with PASC recurrent fever who was found to have a heterozygous mutation in the gene associated with Familial Mediterranean fever (FMF). <h3>Case Description</h3> Our patient presented with recurrent fever 6 months after acute SARs-CoV-2 infection in January 2022. He endorsed prior episodes of unexplained fever and flushing prior but his recurrent fevers (39 C) post COVID had become more frequent occurring every few days. Laboratory analysis when he was afebrile demonstrated normal serum ESR, CRP, and CMP and normal cytokine levels. Genetic (In-Vitae) panel testing for autoinflammatory syndromes revealed a pathogenic heterozygous missense mutation in MEFV (p.A744S), the gene that controls pyrin production. A trial of colchicine was recommended, and he was referred to pediatric rheumatology. <h3>Discussion</h3> FMF is a genetic disorder that causes recurrent episodes of fever and almost always presents before age 20. Clinically significant FMF gene mutations lead to poorly functional pyrin; a protein that controls inflammation. Most children look and feel well between episodes but some children have such frequent episodes that they do not fully recover. In such cases, daily use of Colchicine should be considered as a safe and effective medication to control fever episodes. This report highlights the utility of genetic testing to identify potential causes of recurrent fever after COVID. Children with PASC related recurrent fevers should have genetic testing for susceptibility to FEF as this is a potentially treatable condition.