Untested Relatives Research Articles

Cascade Genetic Risk Education and Testing in Families With Hereditary Cancer Syndromes: A Pilot Study.

Cascade genetic risk evaluation in families with hereditary cancer can reduce the burden of disease but the rate of germline genetic testing in relatives of patients at risk is low. We identified all 277 women diagnosed with breast cancer in Georgia in 2017 who linked to a clinically actionable germline pathogenic variant through a Surveillance, Epidemiology, and End Results registry-variant linkage initiative. We surveyed them, and then invited eligible respondents to an online platform hosted by a navigator that offered cancer genetic risk education and germline genetic testing to untested relatives. We randomly assigned patient-family clusters at the time of the patient enrollment offer to free versus $50 (USD) test cost. Patients invited relatives to join the study through personalized e-mail. Enrolled relatives received online cancer genetic education and the opportunity to order clinical germline genetic testing through the platform. The primary outcome was the number of relatives who ordered genetic testing. One hundred twenty-five of 277 patients completed surveys (45.2%). Most respondents were eligible for the trial offer (113 of 125; 90.4%). In the free testing arm, 20 of 56 eligible patients participated (35.7% of eligible respondents) and they invited 28 relatives: 12 relatives enrolled and 10 ordered testing. In the $50 (USD) arm, 16 of 57 eligible patients participated (28.1%) and they invited 38 relatives: 18 relatives enrolled and 17 ordered testing. Cascade genetic testing in families with hereditary cancer syndromes accrued through a population-based cancer registry can be achieved through an online platform that offers genetic risk education and low-cost testing to relatives. A modest charge did not appear to influence the percentage of participating patients, numbers of participating relatives, and numbers of relatives who received genetic testing.

118 (PB-031) Poster - Information needs of individuals from BRCA-harboring families: A systematic review and content analysis

Background: Accurate and personalized information from reliable sources is paramount for participating in medical decision-making regarding cancer risk management. However, a comprehensive understanding of information needs of individuals from BRCA-harboring families is lacking. To identify information needs of individuals from BRCA-harboring families and compare findings based on demographic (women vs. men) and clinical characteristics (cancer survivors vs. previvors and BRCA-carriers vs. untested relatives).

A pilot study to increase cascade genetic risk education and testing in families with hereditary cancer syndromes.

378 Background: There is great need to build and evaluate tools and strategies to improve cascade genetic risk evaluation in families at high risk for hereditary cancer. The Genetic Information and Family Testing (GIFT) Trial is a population-based intervention that will examine features of a virtual platform that provides genetic risk education (GRE) and low-cost genetic testing (GT) to relatives of 5000 adult patients diagnosed with cancer in 2018-19 in Georgia and California and who tested positive for a clinically actionable germline pathogenic variant (PV). We present findings of a pilot study that informed the GIFT Trial protocol and platform features. Methods: We surveyed 277 women diagnosed with breast cancer in 2017, reported to the Georgia SEER registry, and who tested positive for a clinically actionable PV in a cancer-associated gene. We then invited respondent patients to enroll in the intervention phase which provided online GRE, human pretest genetic navigator support, and an offer of low-cost GT through Color Health, Inc. to all untested 1st or 2nd degree relatives. Respondent patients were eligible for the intervention if they reported a PV on genetic testing and had at least one relative who had not received GT. Enrolled patients invited relatives through the platform by providing email addresses. Family clusters were block randomized to free vs $50 test costs at the time of the initial patient invitation. Results: 125 of 277 patients (45.2%) returned surveys: median age was 51 and 22% were African American. The most common PV reported by patients were BRCA2 (25.7%), BRCA1 (19.5%), CHEK2 (20.4%), ATM (8.8%) and PALB2 (7.1%). Disclosure of genetic test results to relatives was quite high: 83.6% of patients reported that they discussed results with all their daughters vs 69.4% with sons; 78.1% discussed their results with all sisters vs 61.8% with all brothers. The median number of patient-reported untested relatives in a family was 9 (25th-75th percentile: 4-14). Most respondents were eligible for the trial offer (113 of 125, 90.4%). Overall, results were similar between the free test arm and $50 test arm: In the free testing arm, 20 patient participants invited 28 relatives; 12 relatives enrolled, and all 12 relatives ordered testing. In the $50 arm, 16 patient participants invited 38 relatives of whom 18 enrolled and all 18 ordered testing. For the 66 relatives invited by the patient participants: 47 (71.2%) were first degree (8 parents, 22 siblings, and 17 children) and about half of the relatives were men (47.0%). Conclusions: Breast cancer patients with PVs make substantial efforts to communicate with family members about genetic risk but most relatives do not receive GT. Our study findings suggest that a low-cost online navigator-supported intervention can directly engage relatives to increase cascade genetic risk education and testing with little difference in uptake by test cost arms.

A pilot study to increase cascade genetic testing in families with hereditary cancer syndromes.

10602 Background: There is great need to build and evaluate tools and strategies to improve cascade genetic risk evaluation in families at high risk for hereditary cancer. The Genetic Information and Family Testing (GIFT) Trial (CA254822) is a population-based intervention that examines features of a virtual platform that provides genetic risk education (GRE) and low-cost genetic testing (GT) to relatives of adult patients diagnosed with cancer in 2018-19 in Georgia and California and tested positive for a clinically relevant germline pathogenic variant (PV). We present findings of a pilot study intended to inform the GIFT Trial protocol and platform features. Methods: We surveyed 277 women diagnosed with breast cancer in 2017, reported to the Georgia SEER registry, and received genetic testing (95% of whom had a clinically relevant PV). We then invited respondent patients to enroll in the intervention phase which provided online GRE, human pretest genetic navigator support, and an offer of low-cost GT through Color Health, Inc. to all untested 1st or 2nd degree relatives. Respondent patients were eligible for the intervention if they reported a PV on genetic testing and had at least one relative who had not received GT. Enrolled patients invited relatives through the platform by providing email addresses. Family clusters were block randomized to free vs $50 test costs at the time of the initial patient invitation. Results: At study midpoint, 117 of 277 patients (42%) had returned surveys: median age was 51 and 22% were African American. The most frequent PVs reported by the patients were BRCA1/2 (41%), CHEK2 (21%), and PALB2 (8%). Half (54%) had previously encouraged all of their brothers to get GT and 71% had encouraged all of their sisters to get GT. Three-quarters (78%) strongly agreed it was important for relatives to understand their genetic risk for cancer, and half (54%) strongly agreed they would like to make it easier for relatives to get genetic testing. The median number of patient-reported untested relatives in a family was 8.5 (25th-75th percentile: 4-14). Most respondent patients were eligible for the intervention phase (N = 108, 93%). About one-quarter had enrolled in the intervention at midpoint (16 of 53 in no-cost arm vs 16 of 55 in $50 arm). Patients in the no-cost arm invited 21 relatives, 10 of whom had enrolled with 8 ordering GT (38% of invited relatives). Patients in the $50 arm invited 38 relatives, 18 of whom had enrolled with 17 ordering GT (45% of invited relatives). Overall, about half of enrolled relatives (46%) were men. Conclusions: Breast cancer patients with PVs make substantial efforts to communicate with family members about genetic risk; but they strongly endorse the need for additional support to facilitate this complex communication. Interim pilot findings suggest that a low-cost online navigator-supported intervention can directly engage relatives with little difference in GT uptake by test cost arms.

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort.

Simple SummaryThis paper presents important information for the implementation of cascade screening programs for hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The study examined theory-based predictors of index cases’ intention to invite relatives to a family-based cohort, rates of cascade testing among relatives, and preferences of those who carry a pathogenic variant for patient- or provider-mediated communication of testing results to untested relatives. While index cases are equally likely to invite relatives of both genders, males are more likely to not respond to the invitation, especially for HBOC. Findings have implications for tailoring cascade screening programs.Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers’ preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives’ gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services.

NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families

The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH. A further 33 NRXN1 deletions (16 with established phenotype) from the families were identified following cascade screening. Speech and language delay was a consistent clinical presentation. Pedigree analysis of the inherited group revealed numerous untested relatives with a history of mental health and developmental issues, most notably in the NRXN1β isoform patients. Our study highlights the complex nature of the NRXN1 phenotype in this population.

Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography.

Purpose To evaluate a multimodal surveillance regimen including yearly full-field digital (FFD) mammography, dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging, and biannual automated breast (AB) ultrasonography (US) in women with BRCA1 and BRCA2 mutations. Materials and Methods This prospective multicenter trial enrolled 296 carriers of the BRCA mutation (153 BRCA1 and 128 BRCA2 carriers, and 15 women with first-degree untested relatives) between September 2010 and November 2012, with follow-up until November 2015. Participants underwent 2 years of intensified surveillance including biannual AB US, and routine yearly DCE MR imaging and FFD mammography. The surveillance performance for each modality and possible combinations were determined. Results Breast cancer was screening-detected in 16 women (age range, 33-58 years). Three interval cancers were detected by self-examination, all in carriers of the BRCA1 mutation under age 43 years. One cancer was detected in a carrier of the BRCA1 mutation with a palpable abnormality in the contralateral breast. One incidental breast cancer was detected in a prophylactic mastectomy specimen. Respectively, sensitivity of DCE MR imaging, FFD mammography, and AB US was 68.1% (14 of 21; 95% confidence interval [CI]: 42.9%, 85.8%), 37.2% (eight of 21; 95% CI: 19.8%, 58.7%), and 32.1% (seven of 21; 95% CI: 16.1%, 53.8%); specificity was 95.0% (643 of 682; 95% CI: 92.7%, 96.5%), 98.1% (638 of 652; 95% CI: 96.7%, 98.9%), and 95.1% (1030 of 1088; 95% CI: 93.5%, 96.3%); cancer detection rate was 2.0% (14 of 702), 1.2% (eight of 671), and 1.0% (seven of 711) per 100 women-years; and positive predictive value was 25.2% (14 of 54), 33.7% (nine of 23), and 9.5% (seven of 68). DCE MR imaging and FFD mammography combined yielded the highest sensitivity of 76.3% (16 of 21; 95% CI: 53.8%, 89.9%) and specificity of 93.6% (643 of 691; 95% CI: 91.3%, 95.3%). AB US did not depict additional cancers. FFD mammography yielded no additional cancers in women younger than 43 years, the mean age at diagnosis. In carriers of the BRCA2 mutation, sensitivity of FFD mammography with DCE MR imaging surveillance was 90.9% (10 of 11; 95% CI: 72.7%, 100%) and 60.0% (six of 10; 95% CI: 30.0%, 90.0%) in carriers of the BRCA1 mutation because of the high interval cancer rate in carriers of the BRCA1 mutation. Conclusion AB US may not be of added value to yearly FFD mammography and DCE MR imaging surveillance of carriers of the BRCA mutation. Study results suggest that carriers of the BRCA mutation younger than 40 years may not benefit from FFD mammography surveillance in addition to DCE MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Comparison of Chromogenic and ELISA Functional C1 Inhibitor Tests in Diagnosing Hereditary Angioedema

Measuring functional C1 inhibitor (C1 INH) with chromogenic or ELISA methods can confirm a diagnosis of hereditary angioedema (HAE) due to C1 INH deficiency. Previous studies found differences in the agreement of these assays. To evaluate the agreement between chromogenic or ELISA methods in the context of an observational study. Patients with previously confirmed HAE underwent functional C1 INH testing. These patients contacted first-degree relatives (parents, siblings, or offspring) not previously evaluated for HAE, who underwent a panel of complement testing, including for functional C1 INH. Overall, 31 patients with HAE and 46 untested relatives enrolled. Of 46 relatives, 14 (30.4%) were newly diagnosed with HAE based on their laboratory results. Among the 31 patients previously confirmed with HAE, all had low functional C1 INH according to the chromogenic method, whereas 22 (71.0%) had low, 7 (22.6%) had equivocal, and 2 (6.5%) had normal functional C1 INH according to the ELISA method. In the 14 newly diagnosed relatives, all had low functional C1 INH according to the chromogenic method, whereas 11 (78.5%) had low and 3 (21.4%) had equivocal results according to the ELISA method. Despite the apparent discordance in the ELISA and chromogenic assays in a small number of patients, both were useful in measuring functional C1 INH. To establish the diagnosis of HAE due to C1 INH deficiency, functional C1 INH results should be interpreted in combination with family and clinical history, and with other complement tests.

Contralateral breast cancer risk in BRCA1/2-positive families needs to be adjusted for phenocopy rates particularly in second-degree untested relatives

In the previous issue of Breast Cancer Research, Rhiem and colleagues report contralateral breast cancer risks in relatives of BRCA1/2 mutation carriers as well as those testing negative. The authors quote 25-year risks of 44.1% for BRCA1 and 33.5% for BRCA2. The risks quoted are somewhat lower than might be inferred from previous estimates in BRCA1/2 carriers, which have been as high as 40% at 10 years . This discrepancy may be explained in part by the decision to exclude index cases in which there may have been testing bias to bilateral disease. However, the authors dismiss a second bias of including many non-carriers in their analysis as 'putative' carriers.

Family communication matters: The impact of telling relatives about unclassified variants and uninformative DNA-test results

BackgroundUnclassified variant and uninformative BRCA1/2 results are not only relevant for probands to whom results are disclosed but also for untested relatives. Previous studies have seldomly included relatives and have not explained how their lives were influenced by these results. We explored the family communication timeline of genetic counseling: (1) genetic counselors communicate the relatives' cancer risk, (2) probands perceive this risk and (3) communicate this to relatives; (4) relatives perceive this information, and (5) experience an impact on their lives. MethodsWe conducted a retrospective descriptive study in 13 probands with an unclassified variant and 5 with an uninformative result, and in, respectively, 27 and 12 of their untested female relatives from moderate cancer risk families. In questionnaires, probands described their perception of the DNA-test result (i.e., recollections and interpretations of cancer risks and heredity likelihood). Relatives described the communication process, their perception, and impact (i.e., medical decisions, distress, quality of life, and life changes). Bootstrap analysis was used to analyze mediation effects. ResultsThe relatives' own perception strongly predicted breast self-examination, breast/ovarian surveillance or surgery, levels of distress and quality of life, and amount of reported life changes. The extent to which the proband had communicated the DNA-test result in an understandable, direct, reassuring way, predicted the relatives' perception. The actual communicated relatives' cancer risks or the proband's perception did not predict relatives' perception and impact measures. Family characteristics influenced the communication process but not the relatives' perception and outcomes. DiscussionRelatives seem to make poorly informed decisions on the basis of their own perception, which was unrelated to the information that probands had communicated on the basis of the actual communicated result. Therefore, genetic counselors may guide probands in the communication process and may directly inform relatives, if possible. Genet Med 2011:13(4):333–341.

Family tracing to identify patients with Familial Hypercholesterolaemia: the second Audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project

Family tracing is a method recognized to find new patients with familial hypercholesterolaemia (FH). We have implemented family tracing led by FH Nurses and have determined acceptability to patients, feasibility and costs. Nurses were located at five National Health Service (NHS) Trusts; they identified FH patients and offered them family tracing. Responses and test results were recorded on a database and summarized on a family pedigree. The majority ( approximately 70%) of index cases participated; the proportion was lower when patients had been discharged from the clinics and in metropolitan areas. On average, 34% (range 13-50%) of relatives lived outside the catchment area of the clinics and could not attend the nurse-led FH clinics. Of the previously untested relatives, 76% who lived in the catchment area of the clinic came forward to be tested. One-third of the relatives who came forward for testing were children <or=16 y of age. The proportion of relatives diagnosed as likely to have FH was lower than would be predicted (30% vs. 50%). This was mainly due to the uncertainty of a diagnosis based on lipid measurements. The average cost to identify and test one relative was approximately pound 500 but was higher in the metropolitan areas. Cascade testing for FH in the UK is feasible, acceptable and likely to be cost-effective if it is a routine aspect of clinical care. However, national implementation would require an integrated infrastructure, so that all individuals have access to testing, and specialist services for the management of young people.

Malignant Hyperthermia and Day Stay Surgery

Patients who are malignant hyperthermia susceptible are often admitted overnight for observation, even after minor surgery. They may be declined care in a stand-alone day stay unit. This prospective audit set out to investigate whether patients susceptible to malignant hyperthermia can be safely treated as day stay patients. The audit was conducted for four years from late 2000. All patients who were known to be susceptible to malignant hyperthermia, and their untested relatives, who received day stay anaesthesia were included in the audit. Malignant hyperthermia status, age, duration of anaesthesia, anaesthetic technique, type of procedure, intraoperative and postanaesthesia care unit observations and complications were recorded. All patients received a trigger-free anaesthetic technique. Detailed postanaesthesia care unit monitoring was undertaken and patients were observed for two and a half hours postoperatively. Seventy-two patients were included in the audit. General anaesthesia was administered to 85% and regional to 15%. Only minor complications arose in the postoperative period, and none suggested a malignant hyperthermia reaction. Postanaesthesia care unit nursing staff contacted 49 (68%) of the patients the following day, and there was no evidence of malignant hyperthermia reactions. This audit suggests that malignant hyperthermia susceptible patients can be safely managed as day stay patients in appropriate facilities, with appropriate postoperative care.

Screening for hereditary haemochromatosis within families and beyond

Screening programmes for haemochromatosis that include follow-up identification of relatives are claimed to be cost effective. We assessed uptake of screening by first-degree relatives of two groups of index cases: people homozygous for the C282Y mutation ascertained by genetic screening of blood donors; and patients presenting clinically with haemochro matosis. Only 40 (24%) of 165 relatives of blood donors had been tested. By contrast, testing uptake in 121 relatives of patients diagnosed clinically was more than double that (53%), despite unstructured provision of genetic information. A substantial number of untested relatives had undiagnosed iron overload. Overall efficacy of population screening for haemochromatosis is undermined by these observations.

Cancer Incidence in BRCA1 Mutation Carriers

. This study was conducted to determine whether carriers of the BRCA1 gene are also at increased risk of developing cancers than carcinoma of the breast and ovary. A total of 11,847 individual members, male and female, of 699 families identified in the Breast Cancer Linkage Consortium from North America and Western Europe were studied. The numbers and types of cancers found in this cohort were compared with the expected population incidence rates. Male carriers of the BRCA1 gene were found to have an overall cancer rate similar to the expected risk excluding breast cancer. In contrast, female carriers were found to have a significantly increased risk for all cancers than breast and ovary (relative risk [RR] = 2.3, 95% CI = 1.93-2.75, P = .001). For all carriers of the BRCA1 mutation, significantly increased risks were found for cancers of the colon, liver, pancreas, uterus, cervix, and cancers. There were 65 cancers; approximately 20% (N = 12) of these occurred in tested carriers, and the rest occurred in untested relatives of known carriers. Although the expected number of cancers among women in the cohort was 8.6, the actual number was 47 (RR = 9.64, 95% CI = 6.36-14.61, P <.001). Peritoneal cancer was the most frequent of the other cancers, followed by unspecified abdomen or intestinal tract cancers and cancers of female genital organs. In this group, there was no difference in the relative risk according to age. No increased risk for cancers was seen in men. The expected incidence of pancreatic cancer and of cancer of the fallopian tube was not known for all populations; but the incidence was estimated on the basis of actual numbers from smaller population groups. There was a significantly increased risk for these cancers (RR = 44.64, 95% CI = 24.86-80.15, P <.001 for pancreas; RR = 49.94, 95% CI = 22.48-110.94, P <.001 for fallopian tube). The overall risk for all cancers was higher for those less than 65 years of age. For those older than 65, there was no difference in the actual rate and the expected rate in either sex. For men, the risk was not increased for those of any age. However, female carriers of the BRCA1 gene who were less than 65 had an overall increased risk of cancer ((RR = 2.62, 95% CI = 2.15-3.18, P <.001). For younger women the risk of pancreatic cancer was 3.10 (95% CI = 1.43-6.70, P =.008), for cervical cancer the risk was 3.84 (95% CI = 2.33-6.33, P <.001), and for uterine cancer the relative risk was 3.40 (95% CI = 2.13-5.44, P <.001). When BRCA1 carriers in North America and Western Europe were compared, the overall RR was higher for European females (RR = 2.91, 95% CI = 2.32-3.66, P <.001). Likewise, Western European female, but not male, noncarriers had a statistically significant elevated risk of overall cancer compared with North Americans (RR = 1.36, 95% CI = 1.09-1.98). European women were at significantly greater risk for uterine cancer, and North American women had a greater risk for cancer of the cervix. The difference was significant for North American women who did not carry the BRCA1 gene. European men less than 65 years of age were significantly more likely to develop prostate cancer than their North American counterparts (RR = 2.53, 95% CI = 1.10-5.82, P =.026). There were no statistically significant differences seen for men.