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.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorised users.Biomedical Campus, Cambridge, UKGenome sequencing (GS) has been widely adopted by healthcare systems to investigate genomic contributions to rare disease and cancer [1]
Participants: numbers of participants carrying a variant associated with each disease: 16 arrhythmogenic right ventricular cardiomyopathy (ARVC), 1 dilated cardiomyopathy (DCM), 21 hypertrophic cardiomyopathy (HCM), 6 LQTS (Table 1)
Sanger sequencing failed to confirm one variant in one BioResource for rare disease (BRRD) participant, who was not invited to Secondary Cardiac Findings Evaluation (SCARFE)
Summary
Policy around search and return of SF will be informed by clinical actionability, including the positive predictive value of SF in populations not ascertained for the associated health condition This question is more amenable to study in ICC than some other disorders, since disease expression can be assessed in any adult variant carrier through detailed clinical assessment at the time of presentation. Codes of all participants harbouring a likely/highly likely pathogenic variant, together with variant details, were made available to the BRRD, who re-identified participants and assessed for eligibility: age 18–80 years, not known to have a condition associated with the SF, or that might confound clinical test interpretation, and matched with non-carrier controls by age, gender and primary disease cohort. Inclusion of matched non-variant carrier controls allowed us to approach BRRD participants without disclosing variant carrier status, to perform and analyse targeted tests while blind to genotype and to study impacts of the double blind approach on all participants
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