There are several key unsolved issues relating to the clinical use of next generation sequencing, such as: should laboratories report variants of uncertain significance (VUS) to clinicians and/or ...patients? Should they reinterpret VUS in response to growing knowledge in the field? And should patients be recontacted regarding such results? We systematically analyzed 58 consent forms in English used in the diagnostic context to investigate their policies for (a) reporting VUS, (b) reinterpreting variants, including who should initiate this, and (c) recontacting patients and the mechanisms for undertaking any recontact. One-third (20/58) of the forms did not mention VUS in any way. Of the 38 forms that mentioned VUS, only half provided some description of what a VUS is. Approximately one-third of forms explicitly stated that reinterpretation of variants for clinical purposes may occur. Less than half mentioned recontact for clinical purposes, with variation as to whether laboratories, patients, or clinicians should initiate this. We suggest that the variability in variant reporting, reinterpretation, and recontact policies and practices revealed by our analysis may lead to diffused responsibility, which could result in missed opportunities for patients or family members to receive a diagnosis in response to updated variant classifications. Finally, we provide some suggestions for ethically appropriate inclusion of policies for reporting VUS, reinterpretation, and recontact on consent forms.
Genomic sequencing generates huge volumes of data, which may be collected or donated to form large genomic databases. Such information can be stored for future use, either for the data donor ...themselves or by researchers to help improve our understanding of the genetic basis of disease. Creating datasets of this magnitude and diversity is only possible if patients, their families, and members of the public worldwide share their data. However, there is no consensus on the best technical approach to data sharing that also minimises risks to individuals and exploration of stakeholders' views on aspects of genomic data governance models-the ways genomic data is stored, managed, shared and used-has been minimal. To address this need, we conducted focus groups with 39 members of the Australian public exploring their views and preferences for different aspects of genomic data governance models. We found that consent and control were essential to participants, as they wanted the option to choose who had access to their data and for what purposes. Critically, participants wanted a trustworthy body to enforce regulation of data storage, sharing and usage. While participants recognised the importance of data accessibility, they also expressed a strong desire for data security. Finally, financial responsibility for data storage raised concerns for inequity as well as organisations and individuals using data in ethically contentious ways to generate profit. Our findings highlight some of the trade-offs that need to be considered in the development of genomic data governance systems.
CRISPR-Cas9 has revolutionised genome engineering and has the potential to radically change our approach to genetic disease. However, the potential for genetic modification of embryos has raised ...significant and complex ethical and social concerns. The scientific community have called for ongoing stakeholder consultation about Germline Gene Editing (GGE), in particular lay publics, to help guide policy, education, research and regulatory priorities. In response, we conducted a survey to gauge public support for GGE and describe the demographic, experiential and contextual factors that influence individual attitudes. Respondent support was measured across nine hypothetical medical and enhancement GGE applications. We received responses from 1537 participants across 67 countries. Respondents were generally supportive of GGE, particularly for medical applications. While the most opposition observed was among religious respondents, those with work experience in genetics or genomics also reported greater resistance to GGE. Personal or family-related experience with genetics or genomics, identifying as female and tertiary education were also associated with less support for GGE. Further research needs to explore a diverse range of community and group attitudes towards GGE; the reasons underlying demographic and experiential differences; and to determine where the public and genetics professionals draw the line on ethical implementation respectively.
Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to ...systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants.
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of ...Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
The use of genome-wide (whole genome or exome) sequencing for population-based newborn screening presents an opportunity to detect and treat or prevent many more serious early-onset health conditions ...than is possible today.
The Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Working Group reviewed current understanding and concerns regarding the use of genomic technologies for population-based newborn screening and developed, by consensus, eight recommendations for clinicians, clinical laboratory scientists, and policy makers.
Before genome-wide sequencing can be implemented in newborn screening programs, its clinical utility and cost-effectiveness must be demonstrated, and the ability to distinguish disease-causing and benign variants of all genes screened must be established. In addition, each jurisdiction needs to resolve ethical and policy issues regarding the disclosure of incidental or secondary findings to families and ownership, appropriate storage and sharing of genomic data.
The best interests of children should be the basis for all decisions regarding the implementation of genomic newborn screening.
In 2020, the Human Genetics Society of Australasia released its Position Statement on Predictive and Presymptomatic Genetic Testing in Adults and Children. This Position Statement synthesizes the ...major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity and adults living with reduced or fluctuating capacity. Recommendations include that predictive testing in adults, young people and children should only be offered with pretest genetic counseling and the option of posttest genetic counseling. An individual considering (for themselves or on behalf of another) whether to have a predictive test should also be supported to allow them to make an autonomous and informed decision. Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies or other medical interventions in the immediate future. Where symptoms are likely to develop in childhood, in the absence of options to implement surveillance or risk reduction measures, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make their own autonomous and informed decision.
Since the introduction of out-of-hospital health-related genetic tests more than a decade ago, the landscape of genetic testing services has grown in complexity. Although initially most genetic tests ...for health purposes were offered as direct-to-consumer services, that is, without the mediation of a medical professional, currently many commercial providers require that their tests be ordered by a licensed physician. At the same time, some commercially developed health-related genetic tests are gaining support from the professional medical community and are finding their way into clinical practice. Therefore, we differentiated between three types of genetic testing offers: direct-to-consumer, physician-mediated, and clinic-based genetic testing. Expanded carrier screening tests for recessive disorders are currently available through all the three models of genetic testing. Herein, we review the present landscape of expanded carrier screening offers by highlighting the distinct issues associated with each of the three types of genetic testing.
Implementing genomic sequencing into newborn screening programs allows for significant expansion in the number and scope of conditions detected. We sought to explore public preferences and ...perspectives on which conditions to include in genomic newborn screening (gNBS).
We recruited English-speaking members of the Australian public over 18 years of age, using social media, and invited them to participate in online focus groups.
Seventy-five members of the public aged 23-72 participated in one of fifteen focus groups. Participants agreed that if prioritisation of conditions was necessary, childhood-onset conditions were more important to include than later-onset conditions. Despite the purpose of the focus groups being to elicit public preferences, participants wanted to defer to others, such as health professionals or those with a lived experience of each condition, to make decisions about which conditions to include. Many participants saw benefit in including conditions with no available treatment. Participants agreed that gNBS should be fully publicly funded.
How many and which conditions are included in a gNBS program will be a complex decision requiring detailed assessment of benefits and costs alongside public and professional engagement. Our study provides support for implementing gNBS for treatable childhood-onset conditions.
Genomic research can reveal 'unsolicited' or 'incidental' findings that are of potential health or reproductive significance to participants. It is widely thought that researchers have a moral ...obligation, grounded in the duty of easy rescue, to return certain kinds of unsolicited findings to research participants. It is less widely thought that researchers have a moral obligation to actively look for health-related findings (for example, by conducting additional analyses to search for findings outside the scope of the research question).
This paper examines whether there is a moral obligation, grounded in the duty of easy rescue, to actively hunt for genomic secondary findings. We begin by showing how the duty to disclose individual research findings can be grounded in the duty of easy rescue. Next, we describe a parallel moral duty, also grounded in the duty of easy rescue, to actively hunt for such information. We then consider six possible objections to our argument, each of which we find unsuccessful. Some of these objections provide reason to limit the scope of the duty to look for secondary findings, but none provide reason to reject this duty outright.
We argue that under a certain range of circumstances, researchers are morally required to hunt for these kinds of secondary findings. Although these circumstances may not currently obtain, genomic researchers will likely acquire an obligation to hunt for secondary findings as the field of genomics continues to evolve.
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