Secondary findings in inherited heart conditions: a genotype-first feasibility study to assess phenotype, behavioural and psychosocial outcomes

Abstract

Disclosing secondary findings (SF) from genome sequencing (GS) can alert carriers to disease risk. However, evidence around variant-disease association and consequences of disclosure for individuals and healthcare services is limited. We report on the feasibility of an approach to identification of SF in inherited cardiac conditions (ICC) genes in participants in a rare disease GS study, followed by targeted clinical evaluation. Qualitative methods were used to explore behavioural and psychosocial consequences of disclosure. ICC genes were analysed in genome sequence data from 7203 research participants; a two-stage approach was used to recruit genotype-blind variant carriers and matched controls. Cardiac-focused medical and family history collection and genetic counselling were followed by standard clinical tests, blinded to genotype. Pathogenic ICC variants were identified in 0.61% of individuals; 20 were eligible for the present study. Four variant carriers and seven non-carrier controls participated. One variant carrier had a family history of ICC and was clinically affected; a second was clinically unaffected and had no relevant family history. One variant, in two unrelated participants, was subsequently reclassified as being of uncertain significance. Analysis of qualitative data highlights participant satisfaction with approach, willingness to follow clinical recommendations, but variable outcomes of relatives’ engagement with healthcare services. In conclusion, when offered access to SF, many people choose not to pursue them. For others, disclosure of ICC SF in a specialist setting is valued and of likely clinical utility, and can be expected to identify individuals with, and without a phenotype.

Return of individual research results from genomic research: A systematic review of stakeholder perspectives

“…Most participants reported either positive or neutral impacts of receiving results, both when they were related to the study and also for UF/SF [ 9 , 65 , 79 , 153 , 157 , 159 , 174 – 176 , 178 , 179 , 181 , 182 , 185 , 187 , 190 , 191 , 195 ]. A study of 17 research participants and family members who received UF showed that most (16/17) found the process mainly positive or useful and were thankful for being told they have the disease, both for their own wellbeing and also because it provides valuable knowledge for their children [ 153 ].…”

Taking it to the bank: the ethical management of individual findings arising in secondary research

“…For example, researchers in the SCARFE (Secondary Cardiac Findings Evaluation) study are exploring the pathogenicity of genomic variants associated with cardiac disease in individuals whose genomic data are contained in the NIHR BioResource for Rare Disease. 4 Finally, a radiographer at a biobank who acquires an MRI scan from a data contributor and analyses the scan for image quality is not a researcher at all, because she is curating data and not conducting research. (Were the researcher acquiring the scans in the context of a specific research study, this would be primary research).…”

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“…Studies have shown high [87] or moderate to high satisfaction with decisions to receive results [8,174]. Ten studies that asked participants whether they regretted participating in the research showed that either most [175,176] or all of the participant reported little [155] or no regret at taking part and receiving IRR [79,87,174,[177][178][179][180][181]. In fact, a study of 202 participants-comprised of roughly half healthy adults and half patients with either hypertrophic cardiomyopathy or dilated cardiomyopathy-who received health information based on either family history alone or family history and genomic sequencing information, found that those who received genomic results reported lower average levels of decisional regret [182].…”

“…No impact on anxiety or depression [31,180,193] No impact of self-rated health [176] No adverse impact on quality of life [175,176] No psychological harm [83] [194] Low perceived harm [181] No adverse impact on wellbeing [193] No adverse effects on emotions [176] No or little regret [79,87,155,174,[177][178][179][180][181]188] [189]…”

“…Lower regret if chose to receive IRR [155,182] No fatalistic reactions [195] Some distress or worry [80,176,180,186,196,197] Some anxiety and depression [175,179,[198][199][200][201] Lower positive feelings [176] Disappointment [175] Concern [83,175,199] Guilt [180,202] Indifference [175] Uncertainty and confusion [175,176,180,182,203] Increased perception of risk [80, 83] [204] Desire for more results [174,175] https://doi.org/10.1371/journal.pone.0258646.t006…”