Denise Avard

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.

Cohort Profile: The Maternal-Infant Research on Environmental Chemicals Research Platform

BACKGROUND The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. METHODS Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the studys Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. RESULTS Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. CONCLUSIONS The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer

Background and objective: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. Methods: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. Results: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in ⩾2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores ⩾18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score ⩾18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. Conclusion: In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores ⩾18, represents an efficient test in terms of overall cost and sensitivity.

Whole-Genome Sequencing in Newborn Screening Programs

The possible introduction of whole-genome sequencing into newborn screening programs should proceed with caution. The availability of whole-genome sequencing (WGS) is likely to change the practice of population screening programs such as newborn screening (NBS). This Commentary raises key ethical, legal, and social issues surrounding WGS in NBS and suggests a need for deliberation regarding the policy challenges of introducing sequencing in such programs. Any change in the goals of NBS programs should be discussed carefully and should represent the best interests of the child.

Factors influencing intrafamilial communication of hereditary breast and ovarian cancer genetic information

What factors influence intrafamilial communication of hereditary breast and ovarian cancer (HBOC) genetic risk information? Such information can have health implications for individuals who undergo genetic testing, but it can also have implications for their blood relatives. This literature review adopts an ecological model to summarize factors at the individual, familial, and community levels, as well as cross cutting factors relating to the complexity of HBOC genetic information and responsibilities that this information can give rise to. These factors are complex and may result in conflicting senses of responsibility. Faced with the task of communicating HBOC genetic information, the response may be to attempt to balance the potential negative impact of the information on the well-being of the informee (eg, can s/he handle this information?) against the potential health benefit that the knowledge could result in. This balancing represents an effort to reconcile conflicting approaches to protecting family members, and is a moral dilemma. This review sheds light on the factors that contribute to resolve this dilemma.

Returning incidental findings from genetic research to children: views of parents of children affected by rare diseases

Purpose To explore parental perceptions and experiences regarding the return of genomic incidental research findings in children with rare diseases. Methods Parents of children affected by various rare diseases were invited to participate in focus groups or individual telephone interviews in Montreal and Ottawa. Fifteen participants were interviewed and transcriptions were analysed using thematic analysis. Results Four emergent themes underscored parental enthusiasm for receiving incidental findings concerning their childs health: (1) right to information; (2) perceived benefits and risks; (3) communication practicalities: who, when, and how; and (4) service needs to promote the communication of incidental findings. Parents believed they should be made aware of all results pertaining to their childs health status, and that they are responsible for transmitting this information to their child, irrespective of disease severity. Despite potential negative consequences, respondents generally perceived a favourable risk-benefit ratio in receiving all incidental findings. Conclusions Understanding how parents assess the risks and benefits of returning incidental findings is essential to genomic research applications in paediatric medicine. The authors believe the study findings will contribute to establishing future best practices, although further research is needed to evaluate the impact of parental decisions on themselves and their child.

Attitudes of parents toward the return of targeted and incidental genomic research findings in children.

Purpose:We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases.Methods:A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband.Results:Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%).Conclusion:Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.Genet Med 16 8, 633–640.Genetics in Medicine (2014); 16 8, 633–640. doi:10.1038/gim.2013.201

Citizens’ Values Regarding Research With Stored Samples From Newborn Screening in Canada

OBJECTIVES: Newborn screening (NBS) programs may store bloodspot samples and use them for secondary purposes. Recent public controversies and lawsuits over storage and secondary uses underscore the need to engage the public on these issues. We explored Canadian values regarding storage and use of NBS samples for various purposes and the forms of parental choice for anonymous research with NBS samples. METHODS: We conducted a mixed-methods, public engagement study comprising 8 focus groups (n = 60), an educational component, deliberative discussion, and pre- and post-questionnaires assessing knowledge and values toward storage and parental choice. RESULTS: Canadian citizens supported the storage of NBS samples for quality control, confirmatory diagnosis, and future anonymous research (>90%). There was broad support for use of NBS samples for anonymous research; however, opinions were split about the extent of parental decision-making. Support for a “routinized” approach rested on trust in authorities, lack of concern for harms, and an assertion that the population’s interest took priority over the interests of individuals. Discomfort stemmed from distrust in authorities, concern for harms, and prioritizing individual interests, which supported more substantive parental choice. Consensus emerged regarding the need for greater transparency about the storage and secondary use of samples. CONCLUSIONS: Our study provides novel insights into the values that underpin citizens’ acceptance and discomfort with routine storage of NBS samples for research, and supports the need to develop well-designed methods of public education and civic discourse on the risks and benefits of the retention and secondary use of NBS samples.

Clinical Management Recommendations for Surveillance and Risk-Reduction Strategies for Hereditary Breast and Ovarian Cancer Among Individuals Carrying a Deleterious BRCA1 or BRCA2 Mutation

BACKGROUND In Canada, there are wide variations in services for patients at risk for hereditary breast and ovarian cancer (HBOC), and clinical interventions and recommendations differ between regions and/or provinces. National strategies for the clinical management of HBOC exist in the United Kingdom, France, and Australia, and clinical programs in Canada would benefit from similar national recommendations and a consistent approach to clinical management. The National Hereditary Cancer Task Force developed recommendations to address the clinical management of patients at high risk of HBOC and related cancers. These recommendations are based on current practice in high-risk cancer clinics that provide care for individuals with known BRCA1 or BRCA2 mutations. METHODS Canadian consensus recommendations were generated by the National Hereditary Cancer Task Force and compared mainly with two recently published guidance documents on the clinical management of women with increased risk of HBOC, one from the United Kingdom and the other from France. After review of these documents and the associated supporting scientific evidence, the Canadian consensus recommendations were modified and rated using predefined criteria. CONCLUSIONS These recommendations pertain to (1) surveillance options including breast self-examination, clinical breast examination, breast surveillance by imaging, ovarian cancer surveillance, and surveillance for men; (2) risk-reduction strategies including prophylactic mastectomy, prophylactic salpingo-oophorectomy, and pharmacoprevention; and (3) the use of exogenous hormones. Regular updates should occur as new evidence becomes available.

Researchers’ Perceptions of the Ethical Implications of Pharmacogenomics Research with Children

Background: This paper presents the results of an exploratory qualitative study that assesses Canadian pediatric researchers’ perceptions of a pre-selected group of ethical issues raised by pharmacogenomics research with children. Methods: As a pilot study, we conducted semi-structured telephone interviews with Canadian pediatric pharmacogenomic researchers. The interviews were guided by the following themes: (1) benefits and risks of inclusion, (2) the consent/assent process, and (3) the return of research results. Results: Issues about assent, consent, risks and benefits, as well as the communication of results were addressed by the respondents. Some issues, such as the unique vulnerability of children, the long term privacy concerns associated with biobanking, additional core elements that need to be discussed and included in the consent/assent forms, as well as the challenges of communicating research results in a pediatric research were not explicitly identified by the respondents. Conclusion: Further consideration should be given to address the ethical challenges of including children in pharmacogenomics research. This exploratory study indicates that further guidance is needed if children are to be protected and yet benefit from such research.