Additional findings from the 100,000 Genomes Project: A qualitative study of recipient perspectives.

PURPOSE: Participants in the 100,000 Genomes Project, a clinical/research initiative delivered through the UK National Health Service, were offered screening for "additional findings" (AFs): pathogenic/likely pathogenic secondary findings in genes associated with familial hypercholesterolemia or a cancer predisposition syndrome. Understanding the psychological and behavioral responses to secondary findings can inform the clinical utility of a search and disclose policy. METHODS: Thirty-two adult AF recipients took part in semi-structured interviews analyzed using deductive and inductive thematic analysis. RESULTS: Five themes were constructed: cognitive responses to an AF, emotional and psychological responses, personal control, perceived risk of AF-associated disease, and family implications. Many participants had misunderstood or incompletely remembered consent for AFs, and most were surprised or shocked to receive an AF. Although many ultimately appreciated knowing about the risk conferred, some struggled to make sense of their disease risk, which complicated decision making about risk management, particularly for women with a BRCA AF. Recipients sought control through seeking clinical evaluation and information, and informing relatives. Difficulties with conceptualizing risk and lack of AF-associated disease family history meant that some hesitated to inform relatives. CONCLUSION: Genome sequencing programs offering secondary findings require attention to consent processes. Post-disclosure care should aim to promote recipients' perceived personal control.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Direct-to-consumer genetic tests providing health risk information: A systematic review of consequences for consumers and health services.

Direct-to-consumer genetic tests (DTC-GT) offer a variety of genetic health risk information. Understanding evidence of impacts is required for effective policy to protect consumers and healthcare services. We undertook a systematic review according to PRISMA guidelines, searching five literature databases for articles assessing analytic or clinical validity, or reporting consumer or healthcare professional experience with health risk information derived from DTC-GT, published between November 2014 and July 2020. We performed a thematic synthesis to identify descriptive and analytical themes. Forty-three papers met inclusion criteria. Many consumers submit raw DTC-GT data for third-party interpretation (TPI). DTC-GT sometimes report 'false positive' or incorrectly interpreted rare variants, or that such information can result from TPI. Consumers have high expectations of DTC-GT and TPI, and are broadly satisfied, although many do not act on results. A minority of consumers experience adverse psychological impacts. Healthcare consultations can be complex, and professionals have reservations about the validity and utility of DTC-GT-derived information. The contrast between consumer and health professional perceptions can result in mutual dissatisfaction with consultations. Health risk information from DTC-GT and TPI is broadly valued by consumers but presents complex challenges for healthcare services and some consumers.