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

Published version
Peer-reviewed

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Authors

Ormondroyd, Elizabeth  ORCID logo  https://orcid.org/0000-0002-9116-4064
Thomson, Kate L. 
Mackley, Michael P. 
Martin, Jennifer 

Abstract

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.

Description

Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272


Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265


Funder: Rhodes Scholarships; doi: https://doi.org/10.13039/501100000697


Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440


Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274

Keywords

Article, /692/700/139/1512, /692/700, /38/23, article

Journal Title

European Journal of Human Genetics

Conference Name

Journal ISSN

1018-4813
1476-5438

Volume Title

28

Publisher

Springer International Publishing