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1.  Perception, Experience, and Response to Genetic Discrimination in Huntington Disease: The International RESPOND-HD Study 
Genetic discrimination—defined as the denial of rights, privileges, or opportunities or other adverse treatment based solely on genetic information (including family history)—is an important concern to patients, healthcare professionals, lawmakers, and family members at risk for carrying a deleterious gene. Data from the United States, Canada, and Australia were collected from 433 individuals at risk for Huntington disease (HD) who have tested either positive or negative for the gene that causes HD and family members of affected individuals who have a 50% risk for developing the disorder but remain untested. Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation. We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States, Canada, and Australia combined. The incidence of self-reported discrimination is less than the overall worry about the risk of discrimination, which is more prevalent in each domain. Despite a relatively low rate of perceived genetic discrimination in the areas of health insurance and employment, compared to the perception of discrimination and stigma in personal relationships, the cumulative burden of genetic discrimination across all domains of experience represents a challenge to those at risk for HD. The effect of this cumulative burden on daily life decisions remains unknown.
doi:10.1002/ajmg.b.31079
PMCID: PMC3593716  PMID: 20468061
survey; employment; insurance; family history; genetic testing
2.  Improved access to life insurance after genetic diagnosis of familial hypercholesterolaemia: cross-sectional postal questionnaire study 
A decade ago, in the initial stage of genetic testing for familial hypercholesterolaemia (FH) in The Netherlands, it was reported that such screening decreased access to affordable life insurance for mutation carriers. In 2003, in order to improve access to insurance for FH mutation carriers, insurers agreed to underwrite according to a set of guidelines. In this cross-sectional study, we assessed whether access to insurance has improved since the advent of these guidelines. We approached 2825 subjects that had participated in the genetic testing for FH between 1998 and 2003. We compared unconditional acceptance rates before and after FH diagnosis and before and after the guidelines were issued by means of logistic regression analysis. Our study outcome pertains to 414 FH patients who applied for life insurance. Unconditional acceptance of a policy before DNA diagnosis and before the issue of guidelines occurred in 182 out of 255 (71%) cases, versus 27 out of 35 (77%) cases after DNA diagnosis, but before the issue of guidelines. De facto, 107 out of 124 (86%) patients received unconditional acceptance after DNA diagnosis and after the issue of guidelines (P for trend=0.002). Access to life insurance improved for FH patients after molecular diagnosis and it improved even further after the guidelines were issued. Therefore, we argue that limited access to life insurance on the basis of ‘DNA discrimination' is no longer a valid argument against genetic cascade testing for FH, at least not in our country.
doi:10.1038/ejhg.2012.5
PMCID: PMC3376271  PMID: 22293687
familial hypercholesterolemia; hyperlipoproteinemia Type II; genetic testing; genetic testing and adverse effects; life insurance
3.  Unravelling fears of genetic discrimination: an exploratory study of Dutch HCM families in an era of genetic non-discrimination acts 
European Journal of Human Genetics  2012;20(10):1018-1023.
Since the 1990s, many countries in Europe and the United States have enacted genetic non-discrimination legislation to prevent people from deferring genetic tests for fear that insurers or employers would discriminate against them based on that information. Although evidence for genetic discrimination exists, little is known about the origins and backgrounds of fears of discrimination and how it affects decisions for uptake of genetic testing. The aim of this article is to gain a better understanding of these fears and its possible impact on the uptake of testing by studying the case of hypertrophic cardiomyopathy (HCM). In a qualitative study, we followed six Dutch extended families involved in genetic testing for HCM for three-and-a-half years. Semi-structured interviews were conducted with 57 members of these families. Based on the narratives of the families, we suggest that fears of discrimination have to be situated in the broader social and life-course context of family and kin. We describe the processes in which families developed meaningful interpretations of genetic discrimination and how these interpretations affected family members' decisions to undergo genetic testing. Our findings show that fears of genetic discrimination do not so much stem from the opportunity of genetic testing but much more from earlier experiences of discrimination of diseased family members. These results help identify the possible limitations of genetic non-discrimination regulations and provide direction to clinicians supporting their clients as they confront issues of genetic testing and genetic discrimination.
doi:10.1038/ejhg.2012.53
PMCID: PMC3449067  PMID: 22453290
genetic discrimination; fear; insurance; family experiences; hypertrophic cardiomyopathy
4.  The Role of the Geneticist and Genetic Counselor in an ACHD Clinic 
There is a growing population of adults with congenital heart disease due to the advancements in surgical repair and medical management. At the same time, the understanding of the genetic basis of both syndromic and isolated congenital heart disease has grown tremendously and is being rapidly translated into changes in clinical care, resulting in an increasing need for incorporation of genetic expertise into the care of adult congenital heart disease patients. Here we review the importance of delivery of genetic information to the adult congenital heart disease population and highlight the shared and distinct roles of clinical geneticists and genetic counselors in provision of services. The adult congenital heart disease patient population has unique needs and clinical geneticists and genetic counselors can play an important role in the diagnostic evaluation and assessment of these patients to provide an accurate etiologic diagnosis and to counsel regarding genetic testing, recurrence risk, family screening, and prenatal diagnosis.
doi:10.1016/j.ppedcard.2012.05.004
PMCID: PMC3462440  PMID: 23049235
Genetics; genetic counseling; recurrence risk; syndrome
5.  Medical and ethical issues in genetic screening--an academic view. 
Environmental Health Perspectives  1996;104(Suppl 5):987-990.
This article is intended to acquaint those whose principal concerns are the health and safety of workers with genetic screening and some of the medical and ethical issues it raises. Population-based genetic screening increasingly is being considered for predicting future disease in the person being screened. A major problem in screening for alleles that contribute to the development of common, multifactorial disorders is low sensitivity and positive predictive value. In many instances, no demonstrably effective prophylaxis or treatment is available to help those with positive test results. This creates ethical problems of assuring that testing is in the person's best interest and raises in turn issues of autonomy, discrimination, and privacy. Instead of screening for genetic predispositions to harm from workplace exposures, other means of improving the health of workers may bring greater benefits to a higher proportion of workers. The current state of genetic tests for chronic beryllium disease are considered. None are suitable for screening.
PMCID: PMC1469693  PMID: 8933046
6.  A Computational Method to Classify Variants of Uncertain Significance Using Functional Assay Data With Application to BRCA1 
Background
Besides revealing cancer–predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem as ever more patients seek genetic testing for disease syndromes and receive non–informative results from those tests. In cases like the breast–ovarian cancer syndrome where prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical.
Methods
We describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based upon a Bayesian hierarchical model that accounts for sources of experimental heterogeneity.
Results
The functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative.
Conclusions
We demonstrate the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. While the functional data are very informative, they will need to be combined with other forms of data in order to meet the more stringent requirements of clinical application.
Impact
Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers.
doi:10.1158/1055-9965.EPI-10-1214
PMCID: PMC3111818  PMID: 21447777
breast cancer; ovarian cancer; genetic testing; variants of uncertain significance; BRCA1; Bayes classification; functional assay; transcription
7.  CARD4/NOD1 is not involved in inflammatory bowel disease 
Gut  2003;52(1):71-74.
Background and aims: Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex genetic disorders. CARD15/NOD2, a member of the Ced4 superfamily which includes Apaf-1 and CARD4/NOD1, has recently been associated with genetic predisposition to CD but additional genetic factors remain to be identified. Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD.
Patients and methods: The 11 exons of CARD4 were screened for the presence of variants in 63 unrelated IBD patients. The only non-private genetic variation encoding for a substitution in the peptidic chain was genotyped in 381 IBD families (235 CD, 58 UC, 81 mixed, and seven indeterminate colitis families) using a polymerase chain reaction-restriction fragment length polymorphism procedure. Genotyping data were analysed by the transmission disequilibrium test.
Results: Five of nine sequence variations identified in the coding sequence of the gene encoded for non-conservative changes (E266K, D372N, R705Q, T787M, and T787K). Four were present in only one family. The remaining variant (E266K), which exhibited an allele frequency of 0.28, was not associated with CD, UC, or IBD. Furthermore, IBD patients carrying sequence variations in their CARD4 gene had a similar phenotype to those with a normal sequence.
Conclusion: Our results suggest that CARD4 does not play a major role in genetic susceptibility to IBD.
PMCID: PMC1773516  PMID: 12477763
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; CARD4/NOD1; linkage disequilibrium
8.  Progress with genetic cardiomyopathies: Screening, counseling, and testing in dilated, hypertrophic and arrhythmogenic right ventricular dysplasia/cardiomyopathy 
Circulation. Heart failure  2009;2(3):253-261.
Summary
This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy (DCM), with salient features of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.
doi:10.1161/CIRCHEARTFAILURE.108.817346
PMCID: PMC2927103  PMID: 19808347
genetics; cardiomyopathy; genetic testing; genetic counseling
9.  Attitudes and Practices Among Internists Concerning Genetic Testing 
Journal of genetic counseling  2012;22(1):90-100.
Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8%), followed by Breast/Ovarian Cancer (15.0%). In the past 6 months, 65% had counseled patients on genetic issues, 44% had ordered genetic tests, 38.5% had referred patients to a genetic counselor or geneticist, and 27.5% had received ads from commercial labs for genetic testing. Only 4.5% had tried to hide or disguise genetic information, and <2% have had patients report genetic discrimination. Only 53.4% knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7%) and guidelines for genetic testing (87.1%). Most felt needs for more training on when to order tests (79%), and how to counsel patients (82%), interpret results (77.3%), and maintain privacy (80.6%). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p<.001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p<.002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p<.019), counseled patients about genetics, larger practices (p<.032), fewer African-American patients (p<.027), and patients who had reported genetic discrimination (p<.044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests., These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education.
doi:10.1007/s10897-012-9504-z
PMCID: PMC3433636  PMID: 22585186
genetic testing; medical education; doctor-patient communication; ethics; genetic discrimination; decision-making; genetic counseling
10.  Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia 
BMJ : British Medical Journal  2000;321(7275):1497.
Objectives
To assess the feasibility of detecting new cases of heterozygous familial hypercholesterolaemia by using a nurse led genetic register.
Design
Case finding among relatives of patients with familial hypercholesterolaemia.
Setting
Two lipid clinics in central and south Manchester.
Subjects
259 (137 men and 122 women) probands and 285 first degree relatives.
Results
Of the 200 first degree relatives tested, 121 (60%) had inherited familial hypercholesterolaemia. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. Concentrations of serum cholesterol were, respectively, 8.4 (1.7 SD) mmol/l and 8.1 (1.9 SD) mmol/l in affected men and women and 5.6 (1.0 SD) mmol/l and 5.6 (1.1 SD) mmol/l in unaffected men and women. Screening for risk factors as recommended in recent guidelines for coronary heart disease prevention would have failed to identify most of the affected relatives in whom hypertension, diabetes mellitus, cigarette smoking, and obesity were uncommon.
Conclusions
By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolaemia were discovered. Because 1 in 500 people in the UK are affected by this condition, to detect a similar number by population screening over 60 000 tests would be required, and only a few of these patients would have been detected had cholesterol testing been restricted to those with other risk factors for coronary heart disease. A case exists for organising a genetic register approach, linking lipid clinics nationally.
PMCID: PMC27551  PMID: 11118175
11.  Ethical issues in predictive genetic testing: a public health perspective 
Journal of Medical Ethics  2006;32(3):143-147.
As a result of the increase in genetic testing and the fear of discrimination by insurance companies, employers, and society as a result of genetic testing, the disciplines of ethics, public health, and genetics have converged. Whether relatives of someone with a positive predictive genetic test should be notified of the results and risks is a matter urgently in need of debate. Such a debate must encompass the moral and ethical obligations of the diagnosing physician and the patient. The decision to inform or not will vary depending on what moral theory is used. Utilising the utilitarian and libertarian theories produces different outcomes. The principles of justice and non‐maleficence will also play an important role in the decision.
doi:10.1136/jme.2004.010272
PMCID: PMC2564466  PMID: 16507657
genetics; public health; primary care
12.  Intrafamilial disclosure of risk for hereditary breast and ovarian cancer: points to consider 
Journal of Community Genetics  2012;4(2):203-214.
The primary goal of breast and ovarian cancer screening is to minimize the cases of advanced disease and therefore its mortality rate. For hereditary breast and ovarian cancer, one method to reach this goal is to disseminate genetic risk information among family members. However, experience tells us that this information does not always reach family members in a timely manner, if at all. There are many moving parts to a decision to disclose genetic risk information within a family, and the lack of detail and cohesion in current guidelines do a disservice to hereditary breast cancer prevention. Utilizing legal, medical, and policy databases for literature, case law and policy documents relating to communication of genetic test results within families, as well as a consultative process with representative stakeholders, a points to consider has been developed to address a number of issues that might impact the ability and willingness of patients to inform family members of genetic risk. These include: what is “genetic information”; who is the “family”; why should patients inform their family members; and how should health professionals be involved in this process? This represents only an initial step towards fostering better communication within families. Additional research is needed to determine the best methods for encouraging this communication and motivations for disclosing or not and to promote the development of a solution, considering the complexity of human relationships and the probabilistic nature of genetic information.
doi:10.1007/s12687-012-0132-y
PMCID: PMC3666841  PMID: 23275181
Family; Communication; Genetic information; Breast cancer; Intrafamilial
13.  Familial hypercholesterolaemia: pilot study to identify children at risk. 
Journal of Clinical Pathology  1993;46(8):730-733.
AIMS--To evaluate a more effective method of identifying children with familial hypercholesterolaemia by screening a population at high risk. METHODS--Domiciliary measurement of random cholesterol concentration was made in 200 children who were first or second degree relatives of subjects with premature onset coronary artery disease. Measurements were taken by a health visitor using a portable analyser. RESULTS--Twelve new cases of familial hypercholesterolaemia were identified during the first nine months of the study. Random cholesterol concentrations were within the normal range (< 5.2 mmol/l) in 70.5% of samples tested. Forty two (21%) of patients tested had a borderline cholesterol (5.2-5.9 mmol/l) but 50% of these fell within the normal range when fasting capillary samples were analysed. Children with significant hypercholesterolaemia on random testing (concentrations of > 5.9 mmol/l) (8.5%) also had fasting venous blood assayed for high density lipoprotein (HDL) cholesterol and tri-glyceride in the laboratory. Results indicated that 6.5% of patients screened were at high risk of cardiovascular disease (ratio of total: HDL cholesterol of > 4.5), and 1% had a moderately increased risk (ratio 3.5-4.5). CONCLUSIONS--Children with familial hypercholesterolaemia can be identified from a selected "high risk" population by measuring random capillary cholesterol concentration.
PMCID: PMC501458  PMID: 8408697
14.  Identification and treatment of risk factors for coronary heart disease in general practice: a possible screening model 
A screening programme for the identification of risk factors for coronary heart disease in all patients aged 25-55 years in a general practice population was studied.
The identification of risk factors included measurement of obesity, blood pressure, hypercholesterolaemia, and urinalysis, together with questions about family history, cigarette smoking, alcohol intake, and lifestyle. The patients with identified risk factors were invited to attend a lifestyle intervention clinic organised by the practice nurses and run by the health visitors, with the help of the local authority dietitian. Of 2646 (62%) patients who attended for screening, 78 (64%) of the 121 shown to have a high cholesterol concentration experienced a drop in cholesterol concentration. The mean fall in cholesterol concentration in the 78 patients who showed a positive response to intervention was 1·1 mmol/l.
The study was intended as a possible flexible model for screening for coronary heart disease in general practice that could be complemented rather than replaced by opportunistic screening. The issues of organisation, cost, manpower, non-attendance, and effectiveness in a busy general practice environment are discussed.
PMCID: PMC2546139  PMID: 3135890
15.  “In Sickness and in Health”? Disclosures of Genetic Risks in Dating 
Journal of genetic counseling  2010;20(1):98-112.
Individuals who have, or are at risk for, various genetic disorders face many challenges concerning disclosures of genetic information in dating situations. We conducted a qualitative interview study of 64 individuals confronting Huntington’s disease, breast cancer, or Alpha-1 antitrypsin deficiency, examining what issues these individuals encountered, and how they viewed and addressed these—including issues of understandings, privacy, and disclosures of genetic information to various groups (e.g., family members). Incidental to the primary research questions addressed, participants also often described a series of dilemmas in dating situations that they and/or family members, friends, and fellow patients faced of whether to date, and if so, whether, what, how, why, and when to disclose their genetic risk or illness. At times, these individuals feared and experienced rejection, and hence delayed, avoided, or opposed disclosure, or disclosed indirectly or inadvertently. These data are reported in this paper and highlight the importance of patients, their loved ones, genetic counselors, and other health care providers being aware of these issues, and appreciating the complex factors involved, which can affect patients’ coping and social support. This paper, the first to explore several key aspects of disclosures of genetic information in dating, thus suggests needs for public and professional education, and future research in this area.
doi:10.1007/s10897-010-9331-z
PMCID: PMC3152490  PMID: 20890722
Risk communication; Decision-making; Health behaviors; Confidentiality; Ethics; Family relationships; Reproductive choices; Reproductive decisions; Qualitative research
16.  Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic☆ 
Atherosclerosis  2013;229(1):161-168.
Aim
To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate.
Methods
289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication.
Results
An FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 × 10−5) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 × 10−6 respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68).
Conclusions
In this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels.
Highlights
•54 different LDLR mutations found in a cohort of 272 FH probands.•The cohort was found to be genetically heterogeneous with no specific FH mutation.•Mutation detection rate was highly dependent on pre-treatment TC and TG levels.•No difference in specificity/sensitivity between 2 clinical FH diagnosis approaches.•Inadequate LDL-C reduction marks the need for more effective lipid-lowering therapy.
doi:10.1016/j.atherosclerosis.2013.04.011
PMCID: PMC3701838  PMID: 23669246
Cholesterol; Diagnostics; Familial hypercholesterolaemia; Genetic; Lipids; Mutations; FH, familial hypercholesterolaemia; ARMS, amplification refractory mutation system; HRM, high resolution melting; MLPA, multiplex ligation probe-dependent amplification; TC, total cholesterol; TG, triglycerides; CHD, coronary heart disease; DLCN, Dutch Lipid Clinic Network; NGS, next generation sequencing; NICE, National Institute for Health and Clinical Excellence; DFH, definite FH; PFH, possible FH; UH, unclassified hypercholesterolaemia
17.  Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. 
BMJ : British Medical Journal  1991;303(6807):893-896.
OBJECTIVES--(a) To determine the excess mortality from all causes and from coronary heart disease in patients with familial hypercholesterolaemia; (b) to examine how useful various criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes are in identifying these patients. DESIGN--Prospective cohort study. SETTING--Eleven hospital outpatient lipid clinics in the United Kingdom. PATIENTS--282 men and 244 women aged 20-74 with heterozygous familial hypercholesterolaemia. MAIN OUTCOME MEASURE--Standardised mortality ratio, all adults in England and Wales being taken as standard (standardised mortality ratio = 100 for standard population). RESULTS--The cohort was followed up for 2234 person years during 1980-9. Fifteen of the 24 deaths were due to coronary heart disease, giving a standardised mortality ratio of 386 (95% confidence interval 210 to 639). The excess mortality from this cause was highest at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and decreased significantly with age. The standardised mortality ratio for all causes was 183 (117 to 273) and also was highest at age 20-39 (standardised mortality ratio 902; 329 to 1950). There was no significant difference between men and women. Criteria for measurement of cholesterol concentration in cardiovascular screening programmes (family history, presence of myocardial infarction, angina, stroke, corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of these) were present in 78% of patients. CONCLUSIONS--Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients. Criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes identify about three quarters of patients with the clinically overt condition.
PMCID: PMC1671226  PMID: 1933004
18.  Psychological impact of genetic testing for Huntington's disease: an update of the literature 
Genetic testing has been available for Huntington's disease for longer than any other adult onset genetic disorder. The discovery of the genetic mutation causing Huntington's disease made possible the use of predictive testing to identify currently unaffected carriers. Concerns have been raised that predictive testing may lead to an increase in deaths by suicide among identified carriers, and these concerns set in motion research to assess the psychological impact of predictive testing for Huntington's disease. This review article provides an overview of the literature and draws implications for clinical practice. About 10%-20% of people at risk request testing when approached by registries or testing centres. Most of the evidence suggests that non-carriers and carriers differ significantly in terms of short term, but not long term, general psychological distress. Adjustment to results was found to depend more on psychological adjustment before testing than the testing result itself. Although risk factors for psychological sequelae have been identified, few adverse events have been described and no obvious contraindications for testing people at risk have been identified. The psychological impact of testing may depend on whether testing was based on linkage analysis or mutation detection. Cohorts enrolled in mutation detection programmes have higher levels of depression before and after testing, compared with people who sought genetic testing when linkage analysis was available. There is evidence that people who choose to be tested are psychologically selected for a favourable response to testing. The impact of testing on people in settings where less intensive counselling protocols and eligibility criteria are used is unknown, and genetic testing is therefore best offered as part of comprehensive specialist counselling.


doi:10.1136/jnnp.69.5.574
PMCID: PMC1763433  PMID: 11032605
19.  Should we genetically test everyone for haemochromatosis? 
Journal of Medical Ethics  1999;25(2):209-214.
The increasing availability of DNA-based diagnostic tests has raised issues about whether these should be applied to the population at large in order to identify, treat or prevent a range of diseases. DNA tests raise concerns in the community for several reasons. There is the possibility of stigmatisation and discrimination between those who test positive and those who don't. High-risk individuals may be identified for whom no proven effective intervention is possible, or conversely may test "positive" for a disease that does not eventuate. Controversy concerning prenatal diagnosis and termination of affected pregnancies may arise. Haemochromatosis, however, is a disease that is not only treatable but also preventable if those at high risk are identified presymptomatically. This paper will identify and discuss key issues regarding DNA-based population screening for haemochromatosis, and argue that population-based genetic screening for haemochromatosis should be supported when a number of contentious issues are addressed. In the context of a health system with limited resources haemochromatosis is the paradigm of a disorder where there is an ethical and clinical imperative to encourage presymptomatic DNA testing for all in ethnically relevant communities.
PMCID: PMC479209  PMID: 10226930
20.  Risk perception after genetic counseling in patients with increased risk of cancer 
Background
Counselees are more aware of genetics and seek information, reassurance, screening and genetic testing. Risk counseling is a key component of genetic counseling process helping patients to achieve a realistic view for their own personal risk and therefore adapt to the medical, psychological and familial implications of disease and to encourage the patient to make informed choices [1,2].
The aim of this study was to conceptualize risk perception and anxiety about cancer in individuals attending to genetic counseling.
Methods
The questionnaire study measured risk perception and anxiety about cancer at three time points: before and one week after initial genetic counseling and one year after completed genetic investigations. Eligibility criteria were designed to include only index patients without a previous genetic consultation in the family. A total of 215 individuals were included. Data was collected during three years period.
Results
Before genetic counseling all of the unaffected participants subjectively estimated their risk as higher than their objective risk. Participants with a similar risk as the population overestimated their risk most. All risk groups estimated the risk for children's/siblings to be lower than their own. The benefits of preventive surveillance program were well understood among unaffected participants.
The difference in subjective risk perception before and directly after genetic counseling was statistically significantly lower in all risk groups. Difference in risk perception for children as well as for population was also statistically significant. Experienced anxiety about developing cancer in the unaffected subjects was lower after genetic counseling compared to baseline in all groups. Anxiety about cancer had clear correlation to perceived risk of cancer before and one year after genetic investigations.
The affected participants overestimated their children's risk as well as risk for anyone in population. Difference in risk perception for children/siblings as for the general population was significant between the first and second measurement time points. Anxiety about developing cancer again among affected participants continued to be high throughout this investigation.
Conclusion
The participant's accuracy in risk perception was poor, especially in low risk individuals before genetic counseling. There was a general trend towards more accurate estimation in all risk groups after genetic counseling. The importance of preventive programs was well understood. Cancer anxiety was prevalent and associated with risk perception, but decreased after genetic counseling.
[1] National Society of Genetic Counselors (2005), Genetic Counseling as a Profession. Available at (accessed November 25th 2007)
[2] Julian-Reynier C., Welkenhuysen M-, Hagoel L., Decruyenaere M., Hopwood P. (2003) Risk communication strategies: state of the art and effectiveness in the context of cancer genetic services. Eur J of Human Genetics 11, 725-736.
doi:10.1186/1897-4287-7-15
PMCID: PMC2744911  PMID: 19698175
21.  Cholesterol screening and family history of vascular disease. 
Archives of Disease in Childhood  1994;71(3):239-242.
Hypercholesterolaemia is a major risk factor for the development of coronary heart disease (CHD). Early detection and management of hypercholesterolaemia could retard the atherosclerotic process. Given that CHD and hypercholesterolaemia cluster within families, a screening strategy based on a family history of vascular disease has been advocated. Serum total cholesterol concentrations were measured in a random stratified sample of 1012 children aged from 12-15 years old participating in a coronary risk factor surveillance study in Northern Ireland. Information about vascular disease in close family members was obtained by means of a questionnaire. The study population was divided into two groups according to total cholesterol values: (i) normal, < 5.2 mmol/l (n = 822) and (ii) raised, > or = 5.2 mmol/l (n = 190). A family history identified 63 out of 190 individuals with hypercholesterolaemia yielding a sensitivity of 33.2% and specificity of 71.5%. Our data indicated that a strategy whereby only children from high risk families are screened for hypercholesterolaemia is ineffective. While primary prevention emphasising a healthy diet for all is essential, the role of universal screening deserves further appraisal.
PMCID: PMC1029979  PMID: 7979498
22.  Patient decisions for disclosure of secondary findings among the first 200 individuals undergoing clinical diagnostic exome sequencing 
Genetics in Medicine  2013;16(5):395-399.
Purpose:
Exome sequencing of a single individual for a clinical indication may result in the identification of incidental deleterious variants unrelated to the indication for testing (secondary findings). Given the recent availability of clinical exome testing, there is a limited knowledge regarding the disclosure preferences and impact of secondary findings in a clinical diagnostic setting. In this article, we provide preliminary data regarding the preferences for secondary findings results disclosure based on the first 200 families referred to Ambry Genetics for diagnostic exome sequencing.
Methods:
Secondary findings were categorized into four groups in the diagnostic exome sequencing consent: carrier status of recessive disorders, predisposition to later-onset disease, predisposition to increased cancer risk, and early-onset disease. In this study, we performed a retrospective analysis of patient responses regarding the preferences for secondary findings disclosure.
Results:
The majority of patients (187/200; 93.5%) chose to receive secondary results for one or more available categories. Adult probands were more likely than children to opt for blinding of secondary data (16 vs. 4%, respectively). Among responses for blinding, preferences were evenly scattered among categories.
Conclusion:
These data represent the unprecedented results of a large reference laboratory providing clinical exome sequencing. We report, for the first time, the preferences of patients and families for the receipt of secondary findings based on clinical genome sequencing. Overwhelmingly, families undergoing exome sequencing opt for the disclosure of secondary findings. The data may have implications regarding the development of guidelines for secondary findings reporting among patients with severe and/or life-threatening disease undergoing clinical genomic sequencing.
doi:10.1038/gim.2013.153
PMCID: PMC4018499  PMID: 24113345
clinical exome sequencing; genetic testing in minors; incidental findings; return of results; secondary findings
23.  An Online Resource of Digital Stories About Cancer Genetics: Qualitative Study of Patient Preferences and Information Needs 
Background
The Cancer Genetics Service for Wales (CGSW) was established in 1998 as an all-Wales service for individuals with concerns about their family history of cancer. CGSW offers a range of services such as risk assessment, genetic counseling, and genetic testing. Individuals referred to cancer genetics services often have unmet information and support needs, and they value access to practical and experiential information from other patients and health professionals. As a result of the lifelong nature of genetic conditions, a fundamental challenge is to meet the ongoing needs of these patients by providing easily accessible and reliable information.
Objectives
Our aims were to explore how the long-term information and support needs of CGSW patients could be met and to assess whether an online bank of digital stories about cancer genetics would be acceptable to patients.
Methods
In 2009, CGSW organized patient panels across Wales. During these events, 169 patients were asked for their feedback about a potential online resource of digital stories from CGSW patients and staff. A total of 75 patients registered to take part in the project and 23 people from across Wales agreed to share their story. All participants took part in a follow-up interview.
Results
Patient preferences for an online collection of cancer genetics stories were collected at the patient panels. Key topics to be covered by the stories were identified, and this feedback informed the development of the website to ensure that patients’ needs would be met. The 23 patient storytellers were aged between 28 and 75 years, and 19 were female. The digital stories reflect patients’ experiences within CGSW and the implications of living with or at risk of cancer. Follow-up interviews with patient storytellers showed that they shared their experiences as a means of helping other patients and to increase understanding of the cancer genetics service. Digital stories were also collected from 12 members of staff working at CGSW. The digital stories provide reliable and easily accessible information about cancer genetics and are hosted on the StoryBank website (www.cancergeneticsstorybank.co.uk).
Conclusions
The Internet is one mechanism through which the long-term information and support needs of cancer genetics patients can be met. The StoryBank is one of the first places where patient and staff stories have been allied to every aspect of a patient pathway through a service and provides patients with an experiential perspective of the cancer genetics “journey.” The StoryBank was developed in direct response to patient feedback and is an innovative example of patient involvement in service development. The stories are a useful resource for newly referred patients, current patients, the general public, and health care professionals.
doi:10.2196/jmir.1735
PMCID: PMC3222166  PMID: 22057223
Consumer health information; familial cancer; Internet; narrative medicine; patient involvement.
24.  Genetic Testing in Psychiatry: A Review of Attitudes and Beliefs 
Psychiatry  2011;74(4):315-331.
The advent of genetic testing for psychiatric conditions raises difficult questions about when and how the tests should be used. Development of policies regarding these issues may be informed in a variety of ways by the views of key stakeholders: patients, family members, healthcare professionals, and the general public. Here we review empirical studies of attitudes towards genetic testing among these groups. Patients and family members show strong interest in diagnostic and predictive genetic testing, and to a considerable extent psychiatrists share their enthusiasm. Prenatal test utilization seems likely to depend both on parental views on abortion and the seriousness of the disorder. Parents show a surprising degree of interest in predictive testing of children, even when there are no preventive interventions available. Many persons report themselves ready to alter their lifestyles and plans for marriage and family in response to test results. Respondents also fear negative consequences, from discrimination to being unable to cope with knowledge of their “genetic fate.” Empirical studies of beliefs about genetic testing suggest tests are likely to be embraced widely, but the studies have methodologic limitations, reducing the certainty of their conclusions, and indicating a need for further research with more representative samples.
doi:10.1521/psyc.2011.74.4.315
PMCID: PMC3285424  PMID: 22168293
genetic testing; psychiatry; ethics
25.  Should healthcare providers have a duty to warn family members of individuals with an HNPCC‐causing mutation? A survey of patients from the Ontario Familial Colon Cancer Registry 
Journal of Medical Genetics  2007;44(6):404-407.
Background
As genetic testing becomes more common and increasingly intertwined with medical care, the issues of genetic privacy and doctor–patient confidentiality are being examined. Hereditary non‐polyposis colorectal cancer (HNPCC) is a genetic predisposition to colorectal and certain other cancers. Effective screening that can prevent colorectal cancer is an important incentive for genetic testing.
Methods
A survey regarding the duty to warn family members of the risks associated with an HNPCC‐causing mutation was mailed to 227 participants in the Ontario Familial Colon Cancer Registry (OFCCR). To our knowledge, the opinions of patients on this subject have not been reported previously in the literature. Responses were analysed quantitatively using the SAS system and qualitatively by the review of written comments.
Results
Completed surveys were returned by 105 participants, with a response rate of 46.3%. The majority felt a personal responsibility to warn relatives, but there was no significant agreement that doctors or genetic counsellors should have a duty to warn relatives without a patient's permission.
Conclusions
Patients undergoing genetic testing for HNPCC generally understand that relatives could benefit from being informed of genetic risk, but may not be willing or able to inform each family member. Healthcare professionals should engage patients in a discussion of familial implications before genetic testing. An agreement should be formulated regarding which of the relatives should be informed. Patients should be encouraged to personally disseminate the information, given the unrealistic burden on practitioners to perform this task and patients' preference for control over the information.
doi:10.1136/jmg.2006.047357
PMCID: PMC2740891  PMID: 17551085

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