Review: A Scoping Review of Global Guidelines for the Disclosure of Secondary Genomic Findings to Inform the Establishment of Guidelines in China

Genome sequencing provides information about disease risk, prognosis, or treatment response, and is rapidly becoming an affordable and useful tool for patients (1-2). Sequencing occasionally identifies gene variants, called secondary findings (SFs), that are neither relevant to the primary intention of sequencing nor to the patient’s health condition. Disclosure of these SFs to patients is much debated (3-5). Some pathogenic variants are not medically actionable, and the disclosure of these variants may cause the patient anxiety (6), psychological harm (7), or information overload (8). However, non-disclosure of some SFs may miss opportunities to encourage patients to consider life-planning options or accept interventional recommendations (9-10).

The lack of consensus on SF management has led to differences in clinical guidelines across countries (11). For example, the American College of Medical Genetics and Genomics (ACMG) recommends returning SFs that are medically-actionable and have high penetrance, and has published a list of gene-condition pairs that should be returned to patients on a consent basis (12). As a result, disclosure of SFs becomes a preventive strategy to increase health outcomes from genomic interventions, such as population genetic screening and opportunistic screening. In contrast, Canada takes a different approach and recommends avoiding detection and return of SFs to patients (13).

In the era of precision medicine (succinctly described as providing tailored treatments to the right patients), maintenance of public health and development of healthcare technologies have benefited from the accumulation of vast amounts of genomic data worldwide (14). Since SFs contribute a large proportion of the available genomic data, discordance between countries’ SF management and disclosure guidelines may hinder the accumulation of genomic data and the development of precision medicine to address patient- and population-level health (15). In contrast, harmonized international guidelines on disclosing SFs would benefit genomic data accumulation and precision medicine research based on genomics. Therefore, it is useful to examine county-level SF guidelines and their concordance to inform the development of harmonized global guidelines. Such an examination can provide a global landscape of guidelines for stakeholders in China, where no guidelines on SF disclosure currently exist, and can serve as a reference for the establishment of national guidelines.

This scoping review compared clinical guidelines on disclosing SFs derived from genome sequencing. EMBASE, PubMed, MEDLINE, Web of Science, and HumGen, an international database of law and policies related to human genetics (16), were searched for published guidelines. The “grey literature” was searched using Google and Google Scholar. The search terms were “incidental findings,” “secondary findings,” “unanticipated findings,” “unsolicited findings,” “ancillary findings,” “opportunistic findings,” and “accessory findings” (3–4), accompanied by terms related to genome sequencing and communication of results.

The study included documents published by professional organizations, governments, and bioethical committees that were relevant to SF disclosure in a clinical setting. The review was limited to documents written in English and published after 2010, when genome sequencing was initially used. The selection process included two rounds: screening by title and abstract, followed by full-text review (Figure 1).

Figure 1. 

Article selection process.

Characteristics and major contents of the guidelines were extracted from the original documents and included guideline title, source country, publication year, responsible professional organization, and major recommendations. Characteristics and recommendations were summarized by country, separately for adults and children.

To further compare guidelines, the major recommendations were summarized as succinct points, and the guidelines for each jurisdiction were checked for the presence or absence of these points. Results of the presence check were placed in a table to display similarities and differences of the guidelines.

Thirteen articles were included in the review (Table 1) and covered the leading countries in genomics research and practice: the United States (US), the United Kingdom (UK), Canada, Australia, Germany, Denmark, and the European Union (EU). Contents of the clinical guidelines are shown in Table 2.

US: In 2013, the US Presidential Commission for the Study of Bioethical Issues recognized the necessity for professional organizations to guide the management and disclosure of SFs (17). The Commission recommended that patients should be informed of the possibility of SFs, the scope of SFs that will be communicated, and the steps of discovering SFs, and that patient preference not to know SFs should be respected. In response, ACMG published two documents in 2013 (18-19). One document emphasized that patients should be informed of the possibility of finding SFs for which there may be interventions to prevent disease or reduce disease severity. The other document was specific to the reporting of SFs, and provided a list of reportable gene-condition pairs. ACMG recommended that listed variants should be reported regardless of the indication for sequencing and regardless of the age of the patient, including to minors. In 2014, ACMG updated its guidelines with two notable modifications: 1) patients should have the right to opt out of SF detection, and 2) once patients consent to the analysis, the entire list should be analyzed (20). In 2017 and again in 2021, ACMG updated the guidelines and extended the list of gene-disease pairs to additional SFs (12,21). ACMG also recognized that reporting SFs may introduce costs, impact individuals and families, and generate medical, legal, social, and economic ramifications that need to be assessed.

Canada: In 2015, the Canadian College of Medical Geneticists (CCMG) published guidelines that recommended a cautious approach towards the return of SFs to patients (13). Recognizing that reporting SFs is controversial, CCMG recommended focusing on the primary indication of the test, avoiding the discovery of SFs as much as possible. However, CCMG recommended that patients have the option to request and receive SFs.

EU: In 2013, the European Society of Human Genetics (ESHG) published guidelines recommending that SFs that are not interpretable or medically actionable should be avoided (22). However, if an SF indicates a serious health problem and is medically actionable, it should be reported to the patient, overriding the patient’s desire not to know.

UK: In 2014, the PHG Foundation published recommendations suggesting minimizing the generation, interpretation, and disclosure of SFs (23). In the same year, the Association of Genetic Nurses and Counsellors (AGNC) published a position paper stating that patients always have the right to opt-out of receiving SFs and that physicians should only disclose SFs if patients choose to receive them (24).

Germany: The German Ethical Council recognized the possibility of SFs with genome sequencing and recommended that the discovery of SFs should be avoided due to a lack of evidence on its benefits (25). The patient’s right not to know was emphasized.

Australia: In 2014, the Royal College of Pathologists of Australasia (RCPA) published guidelines and recommended that patients should be informed of the types of SFs that may be generated and reported, and have the option of not receiving SFs (26). Without a specific list, RCPA suggested that the return of SFs should be limited to variants that are pathogenic and deemed reportable.

US: ACMG recommended the same policy for children as for adults. That is, once consent is obtained, SFs identified according to the ACMG SF list should be returned to the parents. Parents should have the option of opting out of the analysis for their child. In 2015, the American Society of Human Genetics (ASHG) published a specific position statement for children and adolescents, recommending that physicians should disclose SFs with clinical utility for the child and/or family members if the parents choose to receive them. If the SFs indicate a serious health problem for the child, disclosure should override parental preference.

Canada: CCMG recommended that physicians only return SFs to parents that indicate childhood-onset conditions with high penetrance and medical actionability. Variants that are associated with adult-onset conditions should not be reported, unless the parents want to receive them or disclosure could prevent serious harm to family members’ health.

EU: ESHG stated that benefits to the family members should be considered in a decision to disclose a child’s SF. In 2015, several professional organizations published a joint statement specific to newborn screening programs, recommending use of targeted sequencing to avoid irrelevant findings and focusing on the primary indications for testing (27).

UK: AGNC recommended that detection of children’s SFs associated with adult-onset conditions should be avoided.

Table 3 shows similarities and differences between guidelines from the different countries. In terms of general attitude, the US guidelines take a more positive stance compared with other countries. For example, in the US, physicians have the right to search SFs with patient consent and they should return SFs to patients if the findings are on the ACMG SF list. Guidelines from other countries do not support physicians’ right to search SFs. Instead, they prioritize patients’ right to know or not to know any genomic findings. For children, the US uses the same guidelines used for adults, while the ESHG provides separate recommendations for children.

The studied guidelines are discordant, reflecting three key differences. First, there is insufficient clinical evidence concerning the range of SFs that should be returned to patients. The ACMG guidelines recommend that only SFs associated with monogenic disorders be returned, and that SFs associated with disorders caused by structural variants, repeat expansions, or copy-number variations are insufficiently understood to be listed. Second, the health benefits of returning SFs are not clear. The CCMG guidelines recommend a cautious approach because the benefits of disclosure are not well established. The AGNC statement indicated that robust evidence for the benefits of SFs is needed. Third, there is a lack of evidence for the impact of disclosure on patients, physicians, and the healthcare system. For example, returning SFs that indicate disease risk will probably lead to confirmatory testing. If the disclosure becomes a routine practice for every patient, the downstream costs may become a financial burden for the healthcare system.

This study reviewed clinical guidelines of several countries concerning disclosure of SFs derived from genome sequencing. The review identified discordances between guidelines, as some countries take an open attitude towards disclosure, while others take a more cautious attitude. All guidelines value patient autonomy and the potential benefits of disclosing SFs with high penetrance and medical actionability. Generating new evidence for updating SF management guidelines is warranted.

SFs represent an important source of genomic data and are critically important for genomic research and precision medicine (28). Since the generation of valid evidence on the clinical implications of variants requires much larger datasets than do other medical research areas, it is necessary to collate clinical genome data internationally, including the retrieval of SFs. For example, recent studies usually employ genome data from nearly 300,000 participants (29). Ideally, international genome data should originate from multi-center, multidisciplinary, large-scale studies on a worldwide scale. Therefore, international collaboration on genome data is required.

Considering the significant role of SFs in the accumulated genomic data, globally concordant guidelines on detecting and disclosing SFs would greatly benefit the merging of genome data across countries and support large-scale international collaborations (11). Advances in genomic data accumulation may boost progress in genomic research and precision medicine, and the whole of society may be able to fully harness the benefits of genome sequencing.

Current guidelines recognize that some patients may want SFs returned and some patients may not. Understanding psychological motivations of wanting or not wanting to know SFs may provide important evidence for updating current guidelines. Methods such as discrete choice experiments (DCE) (30–31) and best-worst scaling (BWS) (32–33) would be appropriate tools to investigate psychological motivation (5,34).

Physician preferences on SFs disclosure are also fundamental for clinical guidelines. If physician views are not incorporated, the guidelines may lack consensus and generate much debate among physicians (35). Updated guidelines should consider the circumstances under which physicians decide to return SFs, irrespective of patient preference. It would be valuable to identify factors behind physicians’ decisions and simulate the effect of the factors (5). Regier et al. (2015) and Jiang et al. (2020) utilized DCE to elicit patient and physician preferences towards the return of SFs in Canada (5,36). Generation of more evidence on preferences for disclosure is warranted.

Genomics-based precision medicine is increasingly being studied and used in China to advance healthcare technologies (37). For example, the China Precision Medicine Initiative (CPMI) is accelerating genomic research (38). The lack of guidelines on SF disclosure, however, indicates that precision medicine is at an early stage in China. Physicians and patients have no recommendations to follow when SFs are identified. Professional guidelines are needed to provide support and guidance to SF detection and disclosure in China. This review provides stakeholders in China with a landscape of international guidelines and their similarities and differences that can contribute to the development of guidelines in China.

Cost-effectiveness analysis (CEA) of disclosing SFs is important evidence supporting guideline development. CEA is an established method to inform decision-makers about the value for money of different healthcare technologies, interventions, or policies (39–40). However, CEAs that examine the value of returning SFs face methodological challenges due to the long-term impact of sequencing on quality-of-life and numerous downstream interventions after sequencing (41). Implementation of CEAs on returning SFs in China faces additional challenges, including measurement of quality-of-life, long-term financial impact, the use of modelling techniques to capture the impact of downstream interventions, and appropriate reimbursement thresholds (39,42–43). Researchers may need to overcome methodological difficulties to determine whether disclosing SFs is cost-effective in China. Such economic evidence is of critical importance for decision-makers developing guidelines on SF disclosure.

This study identified differences and similarities between several countries’ clinical guidelines on return of secondary genomic findings to patients. Evidence should be established on which SFs to return, the health benefits of disclosure, and the impact of disclosure on patients, physicians, and the healthcare system.

This study brings attention to the differences between clinical guidelines and supports calls for greater harmonization of guidelines across countries. Concordant guidelines would promote broader international collaboration on genomics and thus may help fully harness the benefits of genome sequencing for all.

This study provides a landscape of international guidelines for stakeholders to use as a reference for developing local guidelines on SF disclosure in China. More economic evaluations on the cost-effectiveness of returning SFs to patients are needed to facilitate the establishment of SF management and disclosure guidelines in China.