At-risk First-degree Relatives Research Articles

Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives

BackgroundCardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). ObjectivesThis study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. MethodsAdult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. ResultsA total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. ConclusionsCardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

Abstract 14707: Electrocardiographic Abnormalities Are Common in DCM Patients’ Family Members With Early Manifestations of DCM

Introduction: Imaging and 12-lead electrocardiogram (ECG) are recommended to screen individuals at risk of dilated cardiomyopathy (DCM). Few studies have examined the yield of ECG testing in these individuals. We hypothesized that ECG abnormalities are more frequent in DCM patients’ family members with early imaging manifestations of DCM than in those without. Methods: The multisite DCM Precision Medicine Study collected contemporaneous imaging and ECG in 1226 First Degree Relatives (FDRs) of DCM patients aged ≥ 18 years between 06/2016 and 04/2021. Imaging results were used to classify participants into four phenotype groups: left ventricular systolic dysfunction alone (LVSD), left ventricular enlargement alone (LVE), DCM (both LVSD and LVE), or normal (neither LVE nor LVSD). ECG status was defined as normal, borderline, or abnormal. Analysis of the probability of a borderline or abnormal ECG result was performed using a generalized linear mixed model accounting for clinical site heterogeneity and intrafamilial correlation. Results: Both imaging and ECG findings were normal in 57% of FDRs. ECG findings were abnormal or borderline in 42% of FDRs with LVSD or LVE and 87% of FDRs with DCM. As shown in Table, FDRs with DCM were more likely than FDRs with no LVE or LVSD to have abnormal or borderline ECGs after adjusting for race, ethnicity, age, sex, and family ascertainment site (OR: 13.17; 95% CI: 5.18 - 33.50). African American FDRs had higher adjusted odds of abnormal or borderline ECG findings than White FDRs (OR: 1.59; 95% CI: 1.15 - 2.20). FDRs in the 4th quartile by age had higher adjusted odds of abnormal or borderline ECG findings than FDRs in the 1st quartile (OR: 4.36; 95% CI: 3.01 - 6.33). Conclusions: An abnormal or borderline ECG was substantially more likely in at-risk FDRs who, by imaging, had DCM. This study supports the use of ECG testing in the screening of FDRs for DCM.

Expansion of Alternative Autoantibodies Does Not Follow the Evolution of Anti-Citrullinated Protein Antibodies in Preclinical Rheumatoid Arthritis: An Analysis in At-Risk First Degree Relatives.

Co-occurrence of autoantibodies specific for ≥1 autoimmune disease is widely prevalent in rheumatoid arthritis (RA) patients. To understand the prevalence of polyautoimmunity in preclinical RA, we performed a comprehensive autoantibody assessment in a First Nations cohort of at-risk first-degree relatives (FDR) of RA patients, a subset of whom subsequently developed RA (progressors). Venous blood was collected from all study participants (n = 50 RA patients and 64 FDR) at scheduled visits, and serum was stored at -20°C. High-sensitivity C-reactive protein level, anti-citrullinated protein antibody (ACPA) status, and autoantibody status were determined using commercially available enzyme-linked immunosorbent assay kits. Rheumatoid factor (RF) was detected by nephelometry. Antinuclear autoantibodies (ANA) were identified using Hep-2 indirect immunofluorescence assay (IFA) and classified according to international consensus nomenclature as various anti-cell (AC) patterns. Of our study cohort, 78.9% had positive ANA reactivity (≥1:80), which was either a homogenous, fine-speckled (AC-1 and AC-4) or mixed IFA pattern. Importantly, the AC-4 and mixed ANA patterns were also observed in progressors at the time of disease onset. While all of the RA patients showed a high prevalence of arthritis-associated autoantibodies, they also had a high prevalence of extractable nuclear antigen-positive autoantibodies to other autoantigens. In FDR, we did not observe any increase in serum autoreactivity to nonarthritis autoantigens, either cross-sectionally or in samples collected longitudinally from progressors prior to RA onset. While alternative autoimmunity and ANA positivity are widely prevalent in First Nations populations, including asymptomatic, seronegative FDR, expansion of alternative autoimmunity does not occur in parallel with ACPA expansion in FDR and is restricted to patients with established RA.

Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses.

Adverse childhood experiences are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of adverse childhood experiences and their relation to the age of onset of major psychiatric conditions in individuals from families that had ⩾2 first-degree relatives with major psychiatric conditions (multiplex families), identified as part of an ongoing longitudinal study. Our sample consisted of 509 individuals from 215 families. Of these, 268 were affected, i.e., diagnosed with bipolar disorder (n = 61), obsessive-compulsive disorder (n = 58), schizophrenia (n = 52), substance dependence (n = 59) or co-occurring diagnoses (n = 38), while 241 were at-risk first-degree relatives who were either unaffected (n = 210) or had other depressive or anxiety disorders (n = 31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire and total adverse childhood experiences exposure and severity scores were calculated. It was seen that affected males, as a group, had the greatest adverse childhood experiences exposure and severity scores in our sample. A Cox mixed effects model fit by gender revealed that a higher total adverse childhood experiences severity score was associated with significantly increased risk for an earlier age of onset of psychiatric diagnoses in males. A similar model that evaluated the interaction of diagnosis revealed an earlier age of onset in obsessive-compulsive disorder and substance dependence, but not in schizophrenia and bipolar disorder. Our study indicates that adverse childhood experiences were associated with an earlier onset of major psychiatric conditions in men and individuals diagnosed with obsessive-compulsive disorder and substance dependence. Ongoing longitudinal assessments in first-degree relatives from these families are expected to identify mechanisms underlying this relationship.

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

BackgroundThe tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear.MethodsWe measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA.ResultsSoluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions.ConclusionsTL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

Communication of genetic information to at-risk relatives during the multidisciplinary monitoring of vascular Ehlers-Danlos syndrome in a French referral clinic.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited disorder leading to arterial, digestive, and uterine complications due to pathogenic COL3A1 variants. Identification of causal variants allows family screening, provided that relatives have previously been informed, according to a 2013 French Decree. The aims of our study were to assess the communication of genetic information to at-risk relatives, the impact of diagnosis disclosure and to highlight a possible link between the experience of vEDS patients and ability to communicate about genetic information. A total of n=51 vEDS adult probands answered a questionnaire during a clinical visit. Communication to relatives was considered effective if the proband gave information to some or all first-degree relatives and considered easily achieved if it was disclosed to all relatives less than a month after the diagnosis and without difficulty. Personal and family vEDS experiences of probands were also assessed. Effective communication of information to relatives was remarkably high (98%). Siblings were the most frequently informed relatives (82%). Women informed their at-risk relatives of genetic family screening faster (p=.006) and easier (p=.004) than men. There was no difference in the disclosure of information to relatives before and after 2013 in our multidisciplinary clinic. Regarding the lived experience of vEDS patients, they felt anxious (78%) at diagnosis disclosure but also considered this diagnosis as an opportunity to start a medical follow-up (82%) putting an end to diagnosis delay. Our findings highlight for the first time that the ability to easily inform at-risk first-degree relatives is related to the relief felt during vEDS-positive diagnosis disclosure (p=.04). In order to improve the communication of genetic information to relatives, we believe that psychological support should systematically be part of the multidisciplinary monitoring, just as medical follow-up and genetic counseling.

Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study

Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia. We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia. We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; p<0·0001) and non-carriers (8 pg/mL [6-11]; p<0·0001), and was higher in converters than in non-converting carriers (19 pg/mL [17-28] vs 8 pg/mL [6-11]; p=0·0007; adjusted for age). During follow-up, NfL increased in converters (b=0·097 [SE 0·018]; p<0·0001). In symptomatic mutation carriers overall, NfL did not change during follow-up (b=0·017 [SE 0·010]; p=0·101) and remained elevated. Rates of NfL change over time were associated with rate of decline in Mini Mental State Examination (b=-94·7 [SE 33·9]; p=0·003) and atrophy rate in several grey matter regions, but not with change in Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale score (b=-3·46 [SE 46·3]; p=0·941). Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker. ZonMw and the Bluefield project.

Circulating levels of free 25(OH)D increase at the onset of rheumatoid arthritis.

ObjectiveEpidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American (INA) population. We therefore profiled the circulating levels of 25-hydroxyvitaminD [25(OH)D], an active metabolite of vitamin D, in a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (progressors).Methods2007 onward, serum samples from INA RA patients and FDR were collected at the time of a structured baseline visit and stored at -20°C. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) and parathyroid hormone (PTH) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry.ResultsWe demonstrate that 25 (OH) D concentrations were lower in winter than summer (P = 0.0538), and that serum 25(OH)D levels were higher in samples collected and stored after 2013 (P<0.0001). Analysis of samples obtained after 2013 demonstrated that 37.6% of study participants were 25(OH)D insufficient (<75nmol/L). Also, seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P<0.05, P<0.01 respectively). Linear regression analysis showed 25(OH)D insufficiency was inversely associated with presence of RA autoantibodies. Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP or PTH levels. Spearman rank correlation analysis showed significant association between 25(OH)D and PTH levels, both in RA patients and progressors at RA onset time.ConclusionWe demonstrate that 25(OH)D levels in serum increased at RA onset in progressors. The potential role that vitamin D metabolites and their downstream effects play in RA transition requires further investigation.

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients.

BackgroundAutoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease.MethodsSamples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated.FindingsAlternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs.InterpretationAutoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies.FundNIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

Dynamic Immune Phenotypes of B and T Helper Cells Mark Distinct Stages of T1D Progression.

Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.

Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative.

In cascade testing, genetic testing for an identified familial pathogenic variant extends to disease-free relatives to allow genetically targeted disease prevention. We evaluated the results of an online initiative in which carriers of 1 of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. In the first year, 1101 applicants invited 2280 first-degree relatives to undergo genetic testing. Of invited relatives, 47.5% (95% confidence interval [CI] = 45.5 to 49.6%) underwent genetic testing, and 12.0% (95% CI = 9.2 to 14.8%) who tested positive continued the cascade by inviting additional relatives to test. Of tested relatives, 4.9% (95% CI = 3.8 to 6.1%) had a pathogenic variant in a different gene from the known familial one, and 16.8% (95% CI = 14.7 to 18.8%) had a variant of uncertain significance. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that up to 5% of the general population may carry a pathogenic variant in 1 of 30 cancer-associated genes.

Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL)

Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of “at-risk” first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.

Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study.

The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives. URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

Explanations of Risk in Families Without Identified Mutations for Hereditary Nonpolyposis Colorectal Cancer

Genetic testing for hereditary forms of cancer does not always identify a causative mutation. Little is known about personal or family response to these indeterminate results when a hereditary form of cancer is suspected. This study explored thoughts about and responses to risk for hereditary nonpolyposis colorectal cancer (HNPCC) when a family member has received indeterminate genetic test results. In this qualitative study, data were gathered from index cases who received indeterminate genetic test results through a longitudinal study offering genetic counseling and testing for HNPCC. First-degree relatives of these indeterminate index cases were also invited to participate in the qualitative interview. Semistructured telephone interviews were conducted with index cases and their at-risk first-degree relatives. Data were analyzed using the within- and across-case method. The across-case analysis led to the development of the Awareness and Surveillance Trajectory, which describes individual interpretations of and responses to risk, based on personal and family history. Explanations of risk addressed the meaning of cancer in the family and provided context for individual interpretations. They were identified using within-case analysis and organized into a typology: innate, exceptional, idiosyncratic, and undeveloped explanations. Members of families without identified HNPCC mutations vary in their explanations for, interpretations of, and responses to indeterminate genetic test results. Explanations of family risk and interpretations of individual risk offer healthcare providers valuable information. In combination with the Awareness and Surveillance Trajectory, assessment of these beliefs can facilitate development of individualized recommendations and strategies for possible preventive actions.

Family history and colorectal cancer screening: a survey of physician knowledge and practice patterns

OBJECTIVES: Risk stratification is essential to effective implementation of colorectal cancer (CRC) screening strategies. The objectives of this study were to assess and compare the current knowledge and practice patterns of gastroenterologists and primary care physicians regarding familial risk of CRC. METHODS: We conducted a survey of regional gastroenterologists and a sample of university- and community-based primary care physicians. The survey instrument assessed physician knowledge of screening recommendations and current practices for individuals with family histories of CRC, adenomatous polyps (APs), familial adenomatous polyposis (FAP), and hereditary nonpolyposis cancer (HNPCC). The instrument also elicited data about familial risk assessment, documentation, and notification of at-risk family members. RESULTS: Thirty-five gastroenterologists (65%) and 58 primary care physicians (92%) completed the survey. Most gastroenterologists and primary care physicians (85% vs 72%) chose age 40 as the appropriate age to begin screening for a family history of CRC, but relatively few (37% vs 36%) recommended screening at age 40 for a family history of APs. Gastroenterologists were significantly more likely to recommend screening for FAP at puberty (80% vs 27%, p < 0.001) and for HNPCC at age 25 (73% vs 50%, p = 0.04). Colonoscopy was the preferred screening strategy by both groups for family histories of CRC (97%), HNPCC (97%), and APs (77%); primary care physicians also preferred colonoscopy for family histories of CRC (72%) and HNPCC (76%) but flexible sigmoidoscopy plus fecal occult blood testing for a family history of APs (38%). Gastroenterologists were more likely to recommend genetic testing for persons at risk of FAP (91% vs 71%, p = 0.03) and HNPCC (72% vs 57%, p = 0.18), routinely inquire about a family history of CRC or APs (93% vs 63%, p < 0.001), and recommend notification of at-risk first-degree relatives with family histories of CRC (94% vs 55%, p < 0.001) or AP (53% vs 6%, p < 0.001). CONCLUSION: Although gastroenterologists are more likely than primary care physicians to elicit a family history of colorectal neoplasia and implement appropriate screening strategies, overall compliance with recommended guidelines and notification of at-risk relatives are suboptimal. Novel approaches for improving awareness of the available screening guidelines are needed.

Ethical principles and pitfalls of genetic testing for dementia.

Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians increase the need for a better understanding of multifaceted issues associated with genetic testing. The genetics of dementia is complex, and genetic testing is fraught with many ethical concerns. Genetic testing can be considered for patients with a family history suggestive of a single gene disorder as a cause of dementia. Testing of affected patients should be accompanied by competent genetic counseling that focuses on probabilistic implications for at-risk first-degree relatives. Predictive testing of at-risk asymptomatic patients should be modeled after presymptomatic testing for Huntington's disease. Testing using susceptibility genes has only a limited diagnostic value at present because potential improvement in diagnostic accuracy does not justify potentially negative consequences for first-degree relatives. Predictive testing of unaffected subjects using susceptibility genes is currently not recommended because individual risk cannot be quantified and there are no therapeutic interventions for dementia in presymptomatic patients.

Lack of communication about familial colorectal cancer risk associated with colorectal adenomas (United States).

Sufficient evidence has accumulated to suggest that the first-degree relatives of patients diagnosed with colorectal adenomas before the age of 60 are at increased risk of colorectal cancer. The principal objective of this study was to assess the extent to which channels of communication exist between physicians, patients and their at-risk first-degree relatives regarding both familial risk and screening recommendations. A telephone survey was conducted among 79 patients (age < or = 60 years) with newly diagnosed colorectal adenomas. Information regarding patient demographics, awareness of familial risk, physician recommendations, and extent of communication with family members about their risk status and need for screening was ascertained. Forty-four (56%) of the 79 eligible subjects completed the survey. Only 18 (41%) responders were aware that their first-degree relatives were at increased risk of colorectal cancer, and the majority claimed to have gained their awareness through sources other than their physicians. Only five (28%) of the 18 knowledgeable patients notified their at-risk relatives of their status, and only two (11%) communicated the need for screening. This survey demonstrates poor communication about familial colorectal cancer risk associated with colorectal adenomas, and highlights the need for novel strategies to both promote awareness and facilitate screening of at-risk relatives.

Detection of Preclinical Parkinson Disease in At-Risk Family Members With Use of [ 123I]β-CIT and SPECT: An Exploratory Study

To explore whether the radioligand 2 beta-carboxymethoxy-3 beta-(4-[123I] iodophenyl) tropane ([123I]beta-CIT) and single-photon emission computed tomography (SPECT) can detect decreased striatal uptake in at-risk relatives of patients with Parkinson disease (PD). Ten PD patients, 10 at-risk first-degree relatives of PD patients, and 10 controls underwent [123I]beta-CIT and SPECT brain imaging. Their striatal uptake ratios were compared. Age-adjusted specific to nonspecific striatal uptake ratios were lower in patients compared with controls and with relatives; however, ratios were similar in relatives and controls. Among relatives, ratios were consistently lower in subgroups postulated to be at higher risk for preclinical PD. Our findings provide preliminary support that [123I]beta-CIT and SPECT may detect decreased striatal uptake in relatives of PD patients postulated to be at higher risk for PD.

Presymptomatic Diagnosis of Neurofibromatosis 2

The clinical spectrum of neurofibromatosis 2 (NF2) at the time of presymptomatic DNA diagnosis in at-risk first-degree relatives in five families were studied at the Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, and the Neurofibromatosis Institute, La Crescenta, CA.

Presymptomatic diagnosis of neurofibromatosis 2 using linked genetic markers, neuroimaging, and ocular examinations.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that causes nervous system tumors and ocular abnormalities such as early-onset lenticular opacities. We assessed the clinical spectrum of NF2 at the time of presymptomatic DNA diagnosis in at-risk first-degree relatives. We studied five multigeneration NF2 families with short tandem repeat markers near the NF2 gene (NF2); gadolinium-enhanced high-resolution magnetic resonance imaging (GE-MRI); and ocular, dermatologic, and neurologic examinations. Eleven of 31 asymptomatic at-risk first-degree relatives were predicted by segregation analysis to be NF2 mutation carriers. Nine of the 11 NF2 mutation carriers were clinically evaluated. Four mutation carriers, including a 7-year-old, had vestibular schwannomas, early-onset cataracts, or both. However, five mutation carriers did not have clinical abnormalities, including a 38-year-old with normal cranial and spinal GE-MRIs and a normal ocular examination. These results indicate that clinical abnormalities can be present in young, but absent in middle-aged, presymptomatic NF2 mutation carriers. By identifying presymptomatic NF2 mutation carriers, DNA diagnosis of NF2 can improve genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.