Purpose:As whole-exome sequencing (WES) and whole-genome sequencing (WGS) move into routine clinical practice, it is timely to review data that might inform the debate regarding secondary findings (SF) and the development of policies that maximize participant benefit.Methods:We systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes.Results:Forty-four articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning “actionable” findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients' views were largely influenced by a sense of rights, whereas views of genomics professionals were informed by a sense of professional responsibility. Experience with genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings.Conclusion:This review suggests that bidirectional interaction during consent might best facilitate informed decision making about SF and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.Genet Med 19 3, 283–293.

IMPORTANCE Retinal detachment with avascularity of the peripheral retina, typically associated with familial exudative vitreoretinopathy (FEVR), can result from mutations in KIF11, a gene recently identified to cause microcephaly, lymphedema, and chorioretinal dysplasia (MLCRD) as well as chorioretinal dysplasia, microcephaly, and mental retardation (CDMMR). Ophthalmologists should be aware of the range of presentations for mutations in KIF11 because the phenotypic distinction between FEVR and MLCRD/CDMMR portends management implications in patients with these conditions. OBJECTIVE To identify gene mutations in patients who present with a FEVR phenotype and explore the spectrum of ocular and systemic abnormalities caused by KIF11 mutations in a cohort of patients with FEVR or microcephaly in conjunction with chorioretinopathy or FEVR. DESIGN, SETTING, AND PARTICIPANTS Clinical data and DNA were collected from each participant between 1998 and 2013 from the clinical practices of ophthalmologists and clinical geneticists internationally. Twenty-eight FEVR probands with diagnoses made by the referring physician and without a known FEVR gene mutation, and 3 with microcephaly and chorioretinopathy, were included. At least 1 patient in each pedigree manifested 1 or more of the following: macular dragging, partial retinal detachment, falciform folds, or total retinal detachment.EXPOSURES Whole-exome sequencing was conducted on affected members in multiplex pedigrees, and Sanger sequencing of the 22 exons of the KIF11 gene was performed on singletons. Clinical data and history were collected and reviewed. MAIN OUTCOMES AND MEASURES Identification of mutations in KIF11.RESULTS Four novel heterozygous KIF11 mutations and 1 previously published mutation were identified in probands with FEVR: p.A218Gfs*15, p.E470X, p.R221G, c.790-1G>T, and the previously described heterozygous p.R47X. Documentation of peripheral avascular areas on intravenous fluorescein angiography was possible in 2 probands with fibrovascular proliferation demonstrating phenotypic overlap with FEVR. CONCLUSIONS AND RELEVANCEMutations in KIF11 cause a broader spectrum of ocular disease than previously reported, including retinal detachment. The KIF11 gene likely plays a role in retinal vascular development and mutations in this gene can lead to clinical overlap with FEVR. Cases of FEVR should be carefully inspected for the presence of microcephaly as a marker for KIF11-related disease to enhance the accuracy of the prognosis and genetic counseling.

PurposeApproaches to secondary findings in genome sequencing (GS) are unresolved. In the United Kingdom, GS is now routinely available through the 100,000 Genomes Project, which offers participants feedback of limited secondary findings.MethodsIn Oxford, a Genomic Medicine Multidisciplinary Team (GM-MDT) governs local access to GS, and reviews findings. Semistructured interviews were conducted with 19 GM-MDT members to explore perspectives on secondary findings.ResultsWhile enthusiastic about GS for diagnosing rare disease, members question the rationale for genome screening largely because of lack of evidence for clinical utility and limited justification for use of resources. Members’ views are drawn from diverse experiences; they feel a strong sense of responsibility to act in participants’ best interests. The capacity to return limited secondary findings should be enabled, but members favor a cautious approach that is responsive to accumulating evidence. Informed participant choice is considered critical, yet challenging. Discrimination of variants is considered essential, and requiring of specialist input and consensus. Multiple areas requiring enhanced engagement and education are identified, i.e., for patients, the public, and health-care professionals; at present, mainstreaming of genomics may be premature.ConclusionUK experts believe that evidence to inform policy toward secondary findings is lacking, arguing for caution.

With large-scale genome sequencing initiatives underway, vast amounts of genomic data are being generated. Results—including secondary findings (SF)—are being returned, although policies around generation and management remain inconsistent. In order to inform relevant policy, it is essential that the views of stakeholders be considered—including participants who have made decisions about SF since the wider debate began. We conducted semi-structured interviews with sixteen rare disease patients and parents enroled in genome sequencing to explore views towards SF. Informed by extensive contact with the healthcare system, interviewees demonstrated high levels of understanding of genetic testing and held pragmatic views: many are content not knowing SF. Interviewees expressed trust in the system and healthcare providers, as well as an appreciation of limited resources; acknowledging existing disease burden, many preferred to focus on their primary condition. Many demonstrated an expectation for recontact and assumed the possibility of later access to initially declined SF. In the absence of such an infrastructure, it is important that responsibilities for recontact are delineated, expectations are addressed, and the long-term impact of decisions is made clear during consent. In addition, some interviewees demonstrated fluid views towards SF, and suggestions were made that perceptions may be influenced by family history. Further research into the changing desirability of SF and behavioural impact of disclosure are needed, and the development and introduction of mechanisms to respond to changes in patient views should be considered.

Whole-exome/whole-genome sequencing (WES/WGS) has the potential to enhance genetic diagnosis of rare disease, and is increasingly becoming part of routine clinical care in mainstream medicine. Effective translation will require ongoing efforts in a number of areas including: selection of appropriate patients, provision of effective consent, pre- and post-test genetic counselling, improving variant interpretation algorithms and practices, and management of secondary findings including those found incidentally and those actively sought. Allied to this is the need for an effective education programme for all members of clinical teams involved in care of patients with rare disease, as well as to maintain public confidence in the use of these technologies. We established a Genomic Medicine Multidisciplinary Team (GM-MDT) in 2014 to build on the experiences of earlier successful research-based WES/WGS studies, to address these needs and to review results including pertinent and secondary findings. Here we report on a qualitative study of decision-making in the GM-MDT combined with analysis of semi-structured interviews with GM-MDT members. Study findings show that members appreciate the clinical and scientific diversity of the GM-MDT and value it for education and oversight. To date, discussions have focussed on case selection including the extent and interpretation of clinical and family history information required to establish likely monogenic aetiology and inheritance model. Achieving a balance between effective use of WES/WGS – prioritising cases in a diverse and highly complex patient population where WES/WGS will be tractable – and meeting the recruitment targets of a large project is considered challenging.