Genetic counselling legislation and practice in cancer in EU Member States.

BACKGROUND: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. METHODS: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. RESULTS: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice. CONCLUSIONS: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

PURPOSE: Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. METHODS: The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. RESULTS: Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. CONCLUSION: Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.

Copy number variations and cognitive phenotypes in unselected populations.

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Lessons learned during the process of reporting individual genomic results to participants of a population-based biobank.

The return of individual genomic results (ROR) to research participants is still in its early phase, and insight on how individuals respond to ROR is scarce. Studies contributing to the evidence base for best practices are crucial before these can be established. Here, we describe a ROR procedure conducted at a population-based biobank, followed by surveying the responses of almost 3000 participants to a range of results, and discuss lessons learned from the process, with the aim of facilitating large-scale expansion. Overall, participants perceived the information that they received with counseling as valuable, even when the reporting of high risks initially caused worry. The face-to-face delivery of results limited the number of participants who received results. Although the participants highly valued this type of communication, additional means of communication need to be considered to improve the feasibility of large-scale ROR. The feedback collected sheds light on the value judgements of the participants and on potential responses to the receipt of genetic risk information. Biobanks in other countries are planning or conducting similar projects, and the sharing of lessons learned may provide valuable insight and aid such endeavors.

Giving and withholding of information following genomic screening: challenges identified in a study of primary care physicians in Estonia.

The use of predictive genomic information to improve medical care remains a contentious topic. However, it is generally agreed that the potential of genomics to improve medicine relies on medical care providers' ability to effectively communicate and put in context the meaning of test results. As the amount of information available increasingly outstrips providers' ability to offer qualified judgments on what the information means, consumers inevitably will be faced with test results of uncertain significance, as well as difficult questions about what they do or do not wish to know. Results of this survey of 64 primary care doctors in Estonia suggests that it may be inherently difficult for physicians to withhold genetic information obtained by genome scans or sequencing, even when they believe that having that information is not in the best interests of their patient. The descriptive data suggest introducing genomic medicine through primary care physicians, as proposed by the Estonian Genome Center of the University of Tartu, will require further genetics education as well as a carefully developed set of guidelines for determining where, when and how to use test results.

Do Biobank Recall Studies Matter? Long-Term Follow-Up of Research Participants With Familial Hypercholesterolemia.

Recall-by-genotype (RbG) studies conducted with population-based biobank data remain urgently needed, and follow-up RbG studies, which add substance to this research approach, remain solitary. In such studies, potentially disease-related genotypes are identified and individuals with those genotypes are recalled for consultation to gather more detailed clinical phenotypic information and explain to them the meaning of their genetic findings. Familial hypercholesterolemia (FH) is among the most common autosomal-dominant single-gene disorders, with a global prevalence of 1 in 500 (Nordestgaard et al., Eur. Heart J., 2013, 34 (45), 3478-3490). Untreated FH leads to lifelong elevated LDL cholesterol levels, which can cause ischemic heart disease, with potentially fatal consequences at a relatively early age. In most cases, the pathogenesis of FH is based on a defect in one of three LDL receptor-related genes-APOB, LDLR, and PCSK9. We present our first long-term follow-up RbG study of FH, conducted within the Estonian Biobank (34 recalled participants from a pilot RbG study and 291 controls harboring the same APOB, LDLR, and PCSK9 variants that were included in the pilot study). The participants' electronic health record data (FH-related diagnoses, lipid-lowering treatment prescriptions) and pharmacogenomic risk of developing statin-induced myopathy were assessed. A survey was administered to recalled participants to discern the impact of the knowledge of their genetic findings on their lives 4-6 years later. Significant differences in FH diagnoses and lipid-lowering treatment prescriptions were found between the recalled participants and controls (34 and 291 participants respectively). Our study highlights the need for more consistent lipid-lowering treatment adherence checkups and encourage more follow-up RbG studies to be performed.

Precise, Genotype-First Breast Cancer Prevention: Experience With Transferring Monogenic Findings From a Population Biobank to the Clinical Setting.

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018-2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer-related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention.

Advances in Genomic Discovery and Implications for Personalized Prevention and Medicine: Estonia as Example.

The current paradigm of personalized medicine envisages the use of genomic data to provide predictive information on the health course of an individual with the aim of prevention and individualized care. However, substantial efforts are required to realize the concept: enhanced genetic discoveries, translation into intervention strategies, and a systematic implementation in healthcare. Here we review how further genetic discoveries are improving personalized prediction and advance functional insights into the link between genetics and disease. In the second part we give our perspective on the way these advances in genomic research will transform the future of personalized prevention and medicine using Estonia as a primer.

Genotype-first approach to the detection of hereditary breast and ovarian cancer risk, and effects of risk disclosure to biobank participants.

Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants' responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.

Correction: Data in question: A survey of European biobank professionals on ethical, legal and societal challenges of biobank research.

[This corrects the article DOI: 10.1371/journal.pone.0221496.].

Data in question: A survey of European biobank professionals on ethical, legal and societal challenges of biobank research.

Biobanks have evolved, and their governance procedures have undergone important transformations. Our paper examines this issue by focusing on the perspective of the professionals working in management or scientific roles in research-based biobanks, who have an important impact on shaping these transformations. In particular, it highlights that recent advances in molecular medicine and genomic research have raised a range of ethical, legal and societal implications (ELSI) related to biobank-based research, impacting directly on regulations and local practices of informed consent (IC), private-public partnerships (PPPs), and engagement of participants. In our study, we investigate the ways that these concerns influence biobanking practices and assess the level of satisfaction of the cross-national biobanking research communities with the ELSI related procedures that are currently in place. We conducted an online survey among biobankers and researchers to investigate secondary use of data, informing and/or re-contacting participants, sharing of data with third parties from industry, participant engagement, and collaboration with industrial partners. Findings highlight the need for a more inclusive and transparent biobanking practice where biobanks are seen in a more active role in providing information and communicating with participants; the need to improve the current IC procedures and the role of biobanks in sharing of samples and data with industry partners and different countries, and the need for practical, tangible and hands-on ethical and legal guidance.

MixFit: Methodology for Computing Ancestry-Related Genetic Scores at the Individual Level and Its Application to the Estonian and Finnish Population Studies.

Ancestry information at the individual level can be a valuable resource for personalized medicine, medical, demographical and history research, as well as for tracing back personal history. We report a new method for quantitatively determining personal genetic ancestry based on genome-wide data. Numerical ancestry component scores are assigned to individuals based on comparisons with reference populations. These comparisons are conducted with an existing analytical pipeline making use of genotype phasing, similarity matrix computation and our addition-multidimensional best fitting by MixFit. The method is demonstrated by studying Estonian and Finnish populations in geographical context. We show the main differences in the genetic composition of these otherwise close European populations and how they have influenced each other. The components of our analytical pipeline are freely available computer programs and scripts one of which was developed in house (available at: www.geenivaramu.ee/en/tools/mixfit).

Reporting incidental findings of genomic disorder-associated copy number variants to unselected biobank participants.

BACKGROUND: Procedural guidelines for disclosure of incidental genomic information are lacking. METHODS: We introduce a method and evaluated the impact of returning results to population biobank participants with 16p11.2 copy number variants, which are commonly associated with neurodevelopmental disorders and BMI imbalance. Of the 7877 participants, 11 carriers were detected. Eight participants were informed of their carrier status and surveyed 11-17 months later. RESULTS: All participants demonstrated preference for disclosure. Although two participants experienced worry, all five survey respondents rated receiving this information favorably. One participant reported modifications in treatment and three felt that their treatment/condition had since improved. CONCLUSION: This approach can be adapted and applied for the return of incidental findings to biobank participants.

Linking a population biobank with national health registries-the estonian experience.

The Estonian population-based biobank, with 52,000 participants' genetic and health data, is the largest epidemiological cohort in the Baltic region. Participants were recruited through a network of medical professionals throughout Estonia (population 1.34 million). Unique legislation as well as a broad consent form give the Estonian Genome Center, a research institute of the University of Tartu, permission to re-contact participants and to retrieve participants' data from national registries and databases. In addition to two re-contacting projects to update the health data of participants, extensive clinical characterizations have been retrieved from national registries and hospital databases regularly since 2010. Acquiring data from electronic health records and registries has provided a means to update and enhance the database of the Genome Center in a timely manner and at low cost. The resulting database allows a wide spectrum of genomic and epidemiological research to be conducted with the aim of benefitting public health. Future plans include linking the genome center database with the national health information system through X-road and exchanging data in real time, as well as using the genetic data and the technical infrastructure available for piloting personalized medicine in Estonia.

Cohort Profile: Estonian Biobank of the Estonian Genome Center, University of Tartu.

The Estonian Biobank cohort is a volunteer-based sample of the Estonian resident adult population (aged ≥18 years). The current number of participants-close to 52000--represents a large proportion, 5%, of the Estonian adult population, making it ideally suited to population-based studies. General practitioners (GPs) and medical personnel in the special recruitment offices have recruited participants throughout the country. At baseline, the GPs performed a standardized health examination of the participants, who also donated blood samples for DNA, white blood cells and plasma tests and filled out a 16-module questionnaire on health-related topics such as lifestyle, diet and clinical diagnoses described in WHO ICD-10. A significant part of the cohort has whole genome sequencing (100), genome-wide single nucleotide polymorphism (SNP) array data (20 000) and/or NMR metabolome data (11 000) available (http://www.geenivaramu.ee/for-scientists/data-release/). The data are continuously updated through periodical linking to national electronic databases and registries. A part of the cohort has been re-contacted for follow-up purposes and resampling, and targeted invitations are possible for specific purposes, for example people with a specific diagnosis. The Estonian Genome Center of the University of Tartu is actively collaborating with many universities, research institutes and consortia and encourages fellow scientists worldwide to co-initiate new academic or industrial joint projects with us.