Disclosure of clinically actionable genetic variants to thoracic aortic dissection biobank participants

Abstract

Background Disclosure of pathogenic variants to thoracic aortic dissection biobank participants was implemented. The impact and costs, including confirmatory genetic testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, were evaluated. Methods We exome sequenced 240 cases with thoracic aortic dissection and 258 controls, then examined 11 aortopathy genes. Pathogenic variants in 6 aortopathy genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 participants, representing 10.8% of the cohort (26/240). A second research sample was used to validate the initial findings. Mailed letters to participants disclosed that a potentially disease causing DNA alteration had been identified (neither the gene nor variant was disclosed). Participants were offered clinical genetic counseling and confirmatory genetic testing in a CLIA laboratory. Results Excluding 6 participants who were deceased or lost to follow-up, 20 participants received the disclosure letter, 10 of whom proceeded with genetic counseling, confirmatory genetic testing, and enrolled in a survey study. Participants reported satisfaction with the letter (4.2 ± 0.7) and genetic counseling (4.4 ± 0.4; [out of 5, respectively]). The psychosocial impact was characterized by low decisional regret (11.5 ± 11.6) and distress (16.0 ± 4.2, [out of 100, respectively]). The average cost for 26 participants was $400, including validation and sending letters. The average cost for those who received genetic counseling and CLIA laboratory confirmation was $605. Conclusions Participants were satisfied with the return of clinically significant biobank genetic results and CLIA laboratory testing; however, the process required significant time and resources. These findings illustrate the trade-offs involved for researchers considering returning research genetic results.

Returning Actionable Genomic Results in a Research Biobank: Analytic Validity, Clinical Implementation and Resource Utilization

“…At 1 month following disclosure, 57/111 (51.4%) responded to the survey, and only one individual scored in the range that suggested regret. The mean score was 8.8 on the 0-100 scale (in which higher scores indicate greater levels of regret), lower than observed in other studies of genetic disclosure to biobank populations 49 . At 6 months, 50/95 individuals (52.6%) responded to the survey with a mean score of 10.8 on the same scale, with 1 individual (a different individual than the 1-month respondent, who did not complete a 6month survey) scoring in the range that suggested regret.…”

“…70; 71 Setting aside the cost of the original research genotyping or sequencing, and ignoring downstream medical costs that might be triggered by the disclosure of the finding, the design, oversight and implementation of our entire gRoR protocol, including laboratory verification of initial GT findings and coverage of CLC cost, was approximately $129,000/year over 4 years, representing about $14 per participant or $3,224 per participant in whom a verified and confirmed result was successfully disclosed. These figures contrast with $605 per participant-disclosure for gRoR for the return of 6 aortopathy genes 49 and $750 per participantdisclosure for a subset of the ACMGv2 gene list in a pediatric biobank. 22 The difference in cost estimates may be because those studies did not actively screen for variants unrelated to participants' presenting diagnoses and omitted most overhead costs (34% of our total estimated costs).…”

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

“…A second Estonian study, in which 16p11.2 CNVs were reported back to 5 carriers, showed most were relieved and were coping with the information, although two said they were slightly worried [ 186 ]. In addition, surveys with ten thoracic aortic dissection biobank participants in the USA who received pathogenic variants showed low levels of psychological distress, negative feelings, uncertainty and privacy concerns [ 188 ].…”

“…Moderate to high satisfaction [8,87,174,184] Relief [9,79,87,153,175,176,185,186] Gratitude [153,176] Increased knowledge [43] Decreased anxiety [43] High rates of wellbeing [8] Positive emotions [187] Low levels of uncertainty [188] [189]…”

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“…Low levels of negative emotions [159,188] Low levels of concern [190,191] No or low levels of distress [83,87,188,192] [189]…”