Exploring Canadian genetic counselors' perspectives and experiences with discussing medical assistance in dying (MAiD).

Medical assistance in dying (MAiD) is the Canadian equivalent of Physician aid-in-dying (PAD) in the United States. Through changes to the eligibility criteria for MAiD in 2021, Canada now has one of the most permissive assisted dying regimens in the world. This study describes Canadian genetic counselors' experiences, knowledge, and preparedness to discuss MAiD with their patients. Survey responses were collected from Canadian genetic counselors (n = 44) and were followed by semi-structured interviews with 14 survey participants. Survey data were analyzed using descriptive statistics, and interview transcripts were analyzed using phronetic iterative analysis and an interpretive description approach. Survey data revealed that genetic counselors have discussed MAiD with patients referred for cancer, neurologic, metabolic, connective tissue, and cardiac indications (n = 18, 40.9%). While most thought that it was important for genetic counselors to be knowledgeable of (n = 41, 93.2%) and prepared to discuss MAiD (n = 43, 97.7%), many were not familiar with the eligibility criteria (n = 27, 61.4%) and the process for accessing MAiD in Canada (n = 29, 65.9%). Interview participants described discussions about MAiD that were initiated by themselves or their patients. Most participants felt prepared to explore a patient's thoughts about MAiD when the patient initiated the discussion but did not feel well-prepared to share detailed information about MAiD. Participants were interested in education and professional guidance to assist them in preparing to discuss MAiD. Learning objectives were developed based on participants' suggestions to assist genetic counselors in their clinical work and self-directed research and to aid in the development of professional guidelines and educational materials for practicing genetic counselors and genetic counseling trainees. As genetic counselors continue engaging in discussions about MAiD, it is critical that these sensitive conversations are approached with increased knowledge and awareness of MAiD legislation, the ethical issues surrounding MAiD in Canada, and relevant patient resources.

Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study.

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals' primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.

TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.

A longitudinal study of magnetic resonance spectroscopy Huntington's disease biomarkers.

Putaminal metabolites examined using cross-sectional magnetic resonance spectroscopy (MRS) can distinguish pre-manifest and early Huntington's Disease (HD) individuals from controls. An ideal biomarker, however, will demonstrate longitudinal change over short durations. The objective here was to evaluate longitudinal in vivo brain metabolite profiles in HD over 24 months. Eighty-four participants (30 controls, 25 pre-manifest HD, 29 early HD) recruited as part of TRACK-HD were imaged at baseline, 12 months, and 24 months using 3T MRS of left putamen. Automated putaminal volume measurement was performed simultaneously. To quantify partial volume effects, spectroscopy was performed in a second, white matter voxel adjacent to putamen in six subjects. Subjects underwent TRACK-HD motor assessment. Statistical analyses included linear regression and one-way analysis of variance (ANOVA). At all time-points N-acetyl aspartate and total N-acetyl aspartate (NAA), neuronal integrity markers, were lower in early HD than in controls. Total NAA was lower in pre-manifest HD than in controls, whereas the gliosis marker myo-inositol (MI) was robustly elevated in early HD. Metabolites were stable over 24 months with no longitudinal change. Total NAA was not markedly different in adjacent white matter than putamen, arguing against partial volume confounding effects in cross-sectional group differences. Total NAA correlations with disease burden score suggest that this metabolite may be useful in identifying neurochemical responses to therapeutic agents. We demonstrate almost consistent group differences in putaminal metabolites in HD-affected individuals compared with controls over 24 months. Future work establishing spectroscopy as an HD biomarker should include multi-site assessments in large, pathologically diverse cohorts.

When access is an issue: exploring barriers to predictive testing for Huntington disease in British Columbia, Canada.

Predictive testing (PT) for Huntington disease (HD) requires several in-person appointments. This requirement may be a barrier to testing so that at risk individuals do not realize the potential benefits of PT. To understand the obstacles to PT in terms of the accessibility of services, as well as exploring mechanisms by which this issue may be addressed, we conducted an interview study of individuals at risk for HD throughout British Columbia, Canada. Results reveal that the accessibility of PT can be a barrier for two major reasons: distance and the inflexibility of the testing process. Distance is a structural barrier, and relates to the time and travel required to access PT, the financial and other opportunity costs associated with taking time away from work and family to attend appointments and the stress of navigating urban centers. The inflexibility of the testing process barrier relates to the emotional and psychological accessibility of PT. The results of the interview study reveal that there are access barriers to PT that deter individuals from receiving the support, information and counseling they require. What makes accessibility of PT services important is not just that it may result in differences in quality of life and care, but because these differences may be addressed with creative and adaptable solutions in the delivery of genetic services. The study findings underscore the need for us to rethink and personalize the way we deliver such services to improve access issues to prevent inequities in the health care system.

Beyond the patient: the broader impact of genetic discrimination among individuals at risk of Huntington disease.

We aimed to address gaps in current understanding of the scope and impact of discrimination, by examining a cohort of individuals at-risk for Huntington disease (HD), to describe the prevalence of concern for oneself and one's family in multiple domains; strategies used to mitigate discrimination; and the extent to which concerns relate to experiences. We conducted a cross-sectional survey of 293 individuals at-risk for HD (80% response rate); 167 respondents were genetically tested and 66 were not. Fear of discrimination was widespread (86%), particularly in the insurance, family and social settings. Approximately half of concerned individuals experienced discrimination (40-62%, depending on genetic status). Concern was associated with "keeping quiet" about one's risk of HD or "taking action to avoid" discrimination. Importantly, concern was highly distressing for some respondents (21% for oneself; 32% for relatives). Overall, concerned respondents with high education levels, who discovered their family history at a younger age, and those who were mutation-positive were more likely to report experiences of discrimination than others who were concerned. Concerns were rarely attributed to genetic test results alone. Concern about genetic discrimination is frequent among individuals at-risk of HD and spans many settings. It influences behavioral patterns and can result in high levels of self-rated distress, highlighting the need for practice and policy interventions. © 2012 Wiley Periodicals, Inc.

Factors associated with experiences of genetic discrimination among individuals at risk for Huntington disease.

The purpose of this study was to identify factors that are associated with experiencing genetic discrimination (GD) among individuals at risk for Huntington disease (HD). Multivariable logistic regression analysis was used to examine factors associated with experiencing GD in data from a cross-sectional, self-report survey of 293 individuals at risk for HD. The study sample comprised 167 genetically tested respondents, and 66 who were not tested (80% response rate). Overall, individuals who learn they are at risk for HD at a younger age (OR = 3.1; 95% CI: 1.5-6.2; P = 0.002), are mutation-positive (OR = 2.8; 95% CI: 1.4-6.0; P = 0.006), or are highly educated (OR = 2.7; 95% CI: 1.4-5.1; P = 0.002) are more likely to experience GD, particularly in insurance, family, and social settings. Further, younger age was associated with discrimination in insurance (OR = 0.97; 95% CI: 0.94-1.00; P = 0.038). This study provides evidence that some people who are at risk for HD were more likely to experience GD than others. Individuals who learned they are at risk for HD at a younger age and those who are mutation-positive were more likely to experience GD, particularly in insurance, family, and social settings. Younger individuals were more likely to experience discrimination in the insurance setting. Overall, highly educated individuals were also more likely to report discrimination. These results provide direction for clinical and family discussions, counseling practice, and policy aimed at mitigating experiences of GD.

Perceptions of genetic discrimination among people at risk for Huntington's disease: a cross sectional survey.

OBJECTIVE: To assess the nature and prevalence of genetic discrimination experienced by people at risk for Huntington's disease who had undergone genetic testing or remained untested. DESIGN: Cross sectional, self reported survey. SETTING: Seven genetics and movement disorders clinics servicing rural and urban communities in Canada. PARTICIPANTS: 233 genetically tested and untested asymptomatic people at risk for Huntington's disease (response rate 80%): 167 underwent testing (83 had the Huntington's disease mutation, 84 did not) and 66 chose not to be tested. MAIN OUTCOME MEASURES: Self reported experiences of genetic discrimination and related psychological distress based on family history or genetic test results. RESULTS: Discrimination was reported by 93 respondents (39.9%). Reported experiences occurred most often in insurance (29.2%), family (15.5%), and social (12.4%) settings. There were few reports of discrimination in employment (6.9%), health care (8.6%), or public sector settings (3.9%). Although respondents who were aware that they carried the Huntington's disease mutation reported the highest levels of discrimination, participation in genetic testing was not associated with increased levels of genetic discrimination. Family history of Huntington's disease, rather than the result of genetic testing, was the main reason given for experiences of genetic discrimination. Psychological distress was associated with genetic discrimination (P<0.001). CONCLUSIONS: Genetic discrimination was commonly reported by people at risk for Huntington's disease and was a source of psychological distress. Family history, and not genetic testing, was the major reason for genetic discrimination.