Shelin Adam

The psychological consequences of predictive testing for Huntington's disease.

Abstract Background. Advances in molecular genetics have led to the development of tests that can predict the risk of inheriting the genes for several adult-onset diseases. However, the psychological consequences of such testing are not well understood. Methods. The 135 participants in the Canadian program of genetic testing to predict the risk of Huntingtons disease were followed prospectively in three groups according to their test results: the increased-risk group (37 participants), the decreased-risk group (58 participants), and the group with no change in risk (the no-change group) (40 participants). All the participants received counseling before and after testing. Standard measures of psychological distress (the General Severity Index of the Symptom Check List 90-R), depression (the Beck Depression Inventory), and well-being (the General Well-Being Scale) were administered before genetic testing and again at intervals of 7 to 10 days, 6 months, and 12 months after the participants received their t...

FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGEs impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally.

Five year study of prenatal testing for Huntington's disease: demand, attitudes, and psychological assessment.

Adult predictive and prenatal testing programmes for Huntingtons disease (HD) in Canada have been available since 1986. However, the demand for prenatal testing and the reasons why some people choose not to have the prenatal test for this late onset disorder have not been well documented. In addition, the knowledge and attitudes of adult predictive testing candidates and their partners about prenatal testing are not well known nor are the psychological effects of prenatal testing well understood. As of September 1991, 425 subjects had entered the Canadian Collaborative Study of Predictive Testing and, of these, 47 subjects or their partners had become pregnant. Of this group, 14 (30%) couples requested prenatal testing, 24 (51%) couples did not want prenatal testing, and nine (19%) at risk subjects had already received a decreased risk through adult predictive testing and, therefore, were not eligible for the prenatal test. Of the 14 couples who initially requested prenatal testing, seven withdrew. Thus, demand for the prenatal test by eligible candidates was 7/38 or 18%, which is much lower than the 32 to 65% expected based on early survey data. The most frequently cited reason for declining prenatal testing was the hope that a cure would be found in time for their children. While the majority of adult predictive testing candidates (71%) in our study had accurate information about definitive prenatal testing, many (63%) did not have a correct understanding of exclusion prenatal testing. Although no serious adverse events such as suicide planning or admission to psychiatric hospital have occurred, a particular need for careful counselling was identified for those at risk candidates and their partners who have one prenatal test and feel compelled to use the test again in future pregnancies. Even though prenatal testing for HD is not requested as often originally expected, it still remains a desired option for some at risk persons and their partners.

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

Purpose and scope The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.

Adverse psychological events occurring in the first year after predictive testing for Huntington's disease. The Canadian Collaborative Study Predictive Testing.

A total of 135 participants in the Canadian predictive testing programme for HD were followed for at least one year in one of four study groups: increased risk (n = 37), decreased risk ( n = 58), uninformative (n = 17), or not tested (n = 23). Clinical criteria for an adverse event were a suicide attempt or formulation of a suicide attempt plan, psychiatric hospitalisation, depression lasting longer than two months, a marked increase in substance abuse, and the breakdown of important relationships. Quantitative criteria, as measured by changes on the General Severity Index of the Symptom Checklist 90-R and the Beck Depression Inventory, were also used to identify people who had adverse events. Twenty of the 135 participants (14.8%) had an adverse event. There were no significant differences between those with or without an adverse event with respect to age, sex, marital status, education, psychiatric history, general psychiatric distress, or social supports at baseline. However, evidence for depression was associated with an increased frequency of adverse events (p < 0.04). The adverse events were similar and seen with equivalent frequency in those receiving an increased risk or decreased risk and persons at risk who did not receive a modification of risk. However, a significant difference was found in the timing of adverse events for the increased and decreased risk groups (p < 0.0002). In the increased risk group all of the adverse events occurred within 10 days after results whereas, in the decreased risk group, all of the adverse events occurred six months or later after reviewing test results. These results suggest that people entering into predictive testing with some evidence of clinical depression warrant special vigilance and also suggest that counselling and support should be available for all participants in predictive testing irrespective of the direction of test results.

Genetics professionals' perspectives on reporting incidental findings from clinical genome-wide sequencing.

Whole exome or whole genome analysis using massively parallel sequencing technologies will undoubtedly solve diagnostic dilemmas; however, incidental findings (IF) that may have medical and social implications will also be discovered. While there is consensus in the literature that analytically valid and medically actionable IF should be returned to patients if requested, there is debate regarding the return of other IF. There are currently no guidelines established for managing IF in the clinical context. We therefore distributed an online questionnaire to 496 geneticists and genetic counselors in Canada to explore this unresolved issue, and 210 professionals participated (response rate = 42%). The proportion of respondents who indicated that they would return IF to patients depended on the nature of the finding, ranging from 95% for information pertaining to a serious and treatable condition to 12% for information with only social implications (e.g., non‐paternity). There was a lack of consensus around the disclosure of certain IF such as genetic carrier status, especially for pediatric patients. The most important considerations identified as impacting IF disclosure included condition‐specific factors such as treatment availability, test accuracy, and evidence indicating pathogenicity. This is the first study to document the views of geneticists and genetic counselors in Canada towards the disclosure of IF, and represents a step towards evidence‐based guidelines for clinical genome‐wide sequencing investigations.

Incidental Findings from Clinical Genome-Wide Sequencing: A Review

There are several unresolved challenges associated with the clinical application of genome-wide sequencing technologies. One of the most discussed issues is incidental findings (IF), which are defined as discoveries made as a result of genetic testing that are unrelated to the indication for the test. The discussion surrounding IF began in the context of research, which we have used to frame consideration of IF in the clinical context. There is growing consensus that analytically valid and medically actionable IF should be offered to patients, but whether and to what extent clinicians should disclose other kinds of IF is debated. While others have systematically reviewed the literature concerning genetic IF, previous reviews focus on ethical and research-related issues and do not consider the implications for the genetic counseling profession specifically. This review discusses the practical considerations, ethical concerns and genetic counseling issues related to IF, with a particular focus on clinical genome-wide sequencing. To date, the bulk of the literature with respect to IF in the clinical context consists of commentaries, reviews and case reports. There is a need for more empirical studies to provide a foundation for institutional protocols and evidence-based clinical practice standards.

Paternalism and the ACMG recommendations on genomic incidental findings: patients seen but not heard

Paternalism and the ACMG recommendations on genomic incidental findings: patients seen but not heard

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

BackgroundArray genomic hybridization is being used clinically to detect pathogenic copy number variants in children with intellectual disability and other birth defects. However, there is no agreement regarding the kind of array, the distribution of probes across the genome, or the resolution that is most appropriate for clinical use.ResultsWe performed 500 K Affymetrix GeneChip® array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip® array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip® array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip® array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.ConclusionAffymetrix GeneChip® 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip® array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip® array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.

Risk Reversals in Predictive Testing for Huntington Disease

The first predictive testing for Huntington disease (HD) was based on analysis of linked polymorphic DNA markers to estimate the likelihood of inheriting the mutation for HD. Limits to accuracy included recombination between the DNA markers and the mutation, pedigree structure, and whether DNA samples were available from family members. With direct tests for the HD mutation, we have assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals. For six such individuals, there was significant disparity between the tests. Three went from a decreased risk to an increased risk, while in another three the risk was decreased. Knowledge of the potential reasons for these changes in results and impact of these risk reversals on both patients and the counseling team can assist in the development of strategies for the prevention and, where necessary, management of a risk reversal in any predictive testing program.