Opt-in for secondary findings as part of diagnostic whole-exome sequencing: Real-life experience from an international diagnostic laboratory.

BACKGROUND: Discussion about the risks and benefits of offering secondary findings as part of genome-wide diagnostics lacks real-life data. We studied the opt-in decisions of patients/families referred to whole exome study (WES) in Blueprint Genetics (BpG), a genetic testing company with customers in over 70 countries to receive secondary findings. Based on the American College of Medical Genetics (ACMG) recommendations for reporting secondary findings, BpG offered testing of specific actionable genes without additional charge for specimens submitted to WES diagnostics. METHODS: Individuals could opt-in for a secondary findings analysis by using a separate electronic consent form. Data from BpG database of electronic consent forms was used for the analysis. RESULTS: During the selected study period there were 3263 WES referrals, from which 2012 were index patients. About half of the individuals (50.4%) opted in to receiving secondary findings. Of patients who opted in, a secondary finding was detected for 2.7%, similar to other studies. We detected huge differences relating to opt-in between individuals from different countries; for instance, 90% of the 41 patients and their family members in Romania opted to receive secondary findings, while none of the 98 patients in Luxembourg chose that option. CONCLUSION: Differences between sexes or between children and adults were small. This data offers one view to the interest of patients and family members to opt in to receiving secondary findings. Research is needed to understand the influence of factors like age, education etc. and possible participation in pre-test counseling to receiving/not receiving secondary findings.

The Finnish genetic heritage in 2022 - from diagnosis to translational research.

Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype-phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

Psychosocial Effects of Receiving Genome-Wide Polygenic Risk Information Concerning Type 2 Diabetes and Coronary Heart Disease: A Randomized Controlled Trial.

Receiving polygenic risk estimates of future disease through health care or direct-to-consumer companies is expected to become more common in the coming decades. However, only a limited number of studies have examined if such estimates might evoke an adverse psychosocial reaction in receivers. The present study utilized data from a sub-section of a personalized medicine project (the P5 study) that combines genomic and traditional health data to evaluate participants' risk for certain common diseases. We investigated how communication of future disease risk estimates related to type 2 diabetes and coronary heart disease influenced respondents' risk perception, self-efficacy, disease-related worry, and other emotions. A randomized controlled trial was conducted, where the experimental group (n = 714) received risk estimates based on traditional and polygenic risk factors and the control group (n = 649) based solely on traditional risk factors. On average, higher disease risk was associated with higher perceived risk (ps, <0.001, ηp 2 = 0.087-0.071), worry (ps <0.001, ηp 2 = 0.061-0.028), lower self-efficacy (p <0 .001, ηp 2 = 0.012), less positive emotions (ps <0.04, ηp 2 = 0.042-0.005), and more negative emotions (ps <0.048, ηp 2 = 0.062-0.006). However, we found no evidence that adding the polygenic risk to complement the more traditional risk factors would induce any substantive psychosocial harm to the recipients (ps >0.06).

Simulating the Genetics Clinic of the Future - whether undergoing whole-genome sequencing shapes professional attitudes.

Whole-genome sequencing (WGS) can provide valuable health insight for research participants or patients. Opportunities to be sequenced are increasing as direct-to-consumer (DTC) testing becomes more prevalent, but it is still fairly unusual to have been sequenced. We offered WGS to fourteen professionals with pre-existing familiarity with an interest in human genetics - healthcare, science, policy and art. Participants received a hard drive containing their personal sequence data files (.BAM,.gvcf), without further explanation or obligation, to consider how experiencing WGS firsthand might influence their professional attitudes. We performed semi-structured pre- and post-sequencing interviews with each participant to identify key themes that they raised after being sequenced. To evaluate how their experience of the procedure evolved over time, we also conducted a questionnaire to gather their views 3 years after receiving their genomic data. Participants were generally satisfied with the experience (all 14 participants would choose to participate again). They mostly decided to participate out of curiosity (personal) and to learn from the experience (professional). Whereas most participants slightly developed their original perspective on genetic data, a small selection of them radically changed their views over the course of the project. We conclude that personal experience of sequencing provides an interesting alternative perspective for experts involved in leading, planning, implementing or researching genome sequencing services. Moreover, the personal experience may provide professionals with a better understanding of the challenges visitors of the Genetics Clinic of the Future may face.

A Web Portal for Communicating Polygenic Risk Score Results for Health Care Use-The P5 Study.

We present a method for communicating personalized genetic risk information to citizens and their physicians using a secure web portal. We apply the method for 3,177 Finnish individuals in the P5 Study where estimates of genetic and absolute risk, based on genetic and clinical risk factors, of future disease are reported to study participants, allowing individuals to participate in managing their own health. Our method facilitates using polygenic risk score as a personalized tool to estimate a person's future disease risk while offering a way for health care professionals to utilize the polygenic risk scores as a preventive tool in patient care.

Perceptions of legislation relating to the sharing of genomic biobank results with donors-a survey of BBMRI-ERIC biobanks.

Biobanks accumulate huge amounts of research findings, including participants' genomic data. Increasingly this leads to biobanks receiving research results that could be of clinical significance to biobank participants. The EU Horizon 2020 Project 'Genetics Clinic of the Future' surveyed European biobanks' perceptions of the legal and regulatory requirements for communicating individual research results to donors. The goal was to gain background knowledge for possible future guidelines, especially relating to the consent process. The Survey was implemented using a web-based Webropol tool. The questionnaire was sent at the end of 2015 to 351 European biobanks in 13 countries that are members of BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium). Seventy-two biobanks responded to the survey, representing each of the 13 BBMRI Member States. Respondents were mainly individuals responsible for the governance of biobanks. The replies indicate that the majority of the respondents thought that their national legislation allowed them to contact participants to communicate results, and that research participants had the right to request their results. However, respondents' understanding of their national legislation varied even within member states. Our results indicate that legislation applied to biobanks in many countries may be scattered and difficult to interpret. In BBMRI-ERIC, there is an ongoing discussion about the need for European recommendations on sharing genomic biobank results with donors, which may pave the way for more coherent global guidelines. Our results form a basis for this work.

Genetics in an isolated population like Finland: a different basis for genomic medicine?

A unique genetic background in an isolated population like that of Finland offers special opportunities for genetic research as well as for applying the genetic developments to the health care. On the other hand, the different genetic background may require local attempts to develop diagnostics and treatment as the selection of diseases and mutations differs from that in the other populations. In this review, we describe the experiences of research and health care in this genetic isolate starting from the identification of specific monogenic diseases enriched in the Finnish population all the way to implementing the knowledge of the unique genetic background to genomic medicine at population level.

Challenges raised by cross-border testing of rare diseases in the European union.

As the availability of genetic tests has grown rapidly during the last decade along with the increasing knowledge of the genetic background of rare inherited diseases, sending DNA samples to another country for analysis has become more of a routine than an exception in clinical diagnostics. Nonetheless, few studies of cross-border genetic testing of rare diseases in the European Union (EU) have been carried out, and data about the challenges and problems related to cross-border testing are lacking. The purpose of this study was to investigate the experiences of the molecular genetic laboratories and the clinical genetics units concerning the cross-border genetic testing of rare diseases in the Member States of the EU. Data were collected using web-based questionnaires and phone interviews targeted at laboratories and clinical units registered with the Orphanet database. The specific aims were to clarify the volume, quality and challenges of cross-border genetic testing. The results revealed, for example, that the variability of the required documentation creates confusion and, unexpectedly, sample dispatch was considered a major problem in cross-border testing. In addition, the differences between countries regarding the reimbursement and authorization policies of cross-border testing were significant, thus confirming the pre-existing assumption about unequal access to genetic testing in the different Member States. To facilitate and organize cross-border testing, common practices need to be created at the level of the EU, and follow-up studies are needed to monitor their effects.

Family history and perceived risk of diabetes, cardiovascular disease, cancer, and depression.

BACKGROUND: Family history is a useful and inexpensive tool to assess risks of multifactorial diseases. Family history enables individualized disease prevention, but its effects on perceived risks of various diseases need to be understood in more detail. We examined how family history relates to perceived risk of diabetes mellitus, cardiovascular disease (CVD), cancer, and depression, and whether these associations are independent of or moderated by sociodemographic factors, health behavior/weight status (smoking, alcohol consumption, physical activity, BMI [kg/m(2)]), or depressive symptoms. METHODS: Participants were Finnish 25-74-year-olds (N=6258) from a population-based FINRISK 2007 study. Perceived absolute lifetime risks (Brewer et al., 2004; Becker, 1974; Weinstein and Nicolich, 1993; Guttmacher et al., 2004; Yoon et al., 2002) and first-degree family history of CVD, diabetes, cancer and depression, and health behaviors were self-reported. Weight and height were measured in a health examination. RESULTS: Family history was most prevalent for cancer (36.7%), least for depression (19.6%). Perceived risk mean was highest for CVD (2.8), lowest for depression (2.0). Association between family history and perceived risk was strongest for diabetes (ß=0.34, P<0.001), weakest for depression (ß=0.19, P<0.001). Adjusting for sociodemographics, health behavior, and depressive symptoms did not change these associations. The association between family history and perceived risk tended to be stronger among younger than among older adults, but similar regardless of health behaviors or depressive symptoms. DISCUSSION: Association between family history and perceived risk varies across diseases. People's current understandings on heritability need to be acknowledged in risk communication practices. Future research should seek to identify effective strategies to combine familial and genetic risk communication in disease prevention.

Epidemiology of early-onset Parkinson's disease in Finland.

OBJECTIVE: The contribution of genetic causes to Parkinson's disease (PD) is strongest in early-onset cases. We ascertained a nationwide cohort of patients in order to study the genetic epidemiology of early-onset PD (EOPD) in Finland. METHODS: By means of a search in a national database we ascertained all patients with EOPD. These patients had become eligible for reimbursement of PD drugs between the years 1995-2006 and were <55 years of age at the time of PD diagnosis. A total of 441 patients consented and provided clinical and genealogical information. RESULTS: The incidence of EOPD increased 1.7-fold between the years 1995-2006, the mean annual incidence being 3.3/100,000. Fifty-two patients (11.8%) reported an affected first-degree relative. The birthplaces of patients with PD among first-degree relatives were clustered in certain regions in the southwestern and western coastal provinces of Finland and in the eastern province of Savo. Furthermore, the distance between the birthplaces of the patients' parents was smaller for patients, who had first-degree relatives with PD than for patients with no family history of PD. CONCLUSIONS: Our data suggest that the incidence of EOPD is increasing. The birthplaces of patients with PD among first-degree relatives were clustered in certain provinces of Finland suggesting that monogenic forms of PD or genetic susceptibility of PD are present in the population.

Genetic causal beliefs about morbidity: associations with health behaviors and health outcome beliefs about behavior changes between 1982-2002 in the Finnish population.

BACKGROUND: The role and meaning of genetic information has grown considerably in the recent decades. We examined changes in causal beliefs about morbidity as well as the associations between causal beliefs, health behaviors and obesity, and health outcome beliefs from 1982 to 2002. METHODS: In five population-based risk-factor surveys (the FINRISK Studies) of individuals aged 25 to 64 years conducted from 1982 to 2002 (n = 37,503), respondents chose the most important cause of morbidity from a list of ten alternatives. Health outcome beliefs were assessed with two items. Physical inactivity and smoking status were based on self-reports and obesity was based on measured height and weight. RESULTS: The prevalence of those who endorse genetic factors as the most important cause of morbidity increased from 4% in 1982 to 10% in 1992 and remained at that level until 2002. During the study period, lack of exercise and overweight increased, whereas inappropriate diet and stress diminished as causal beliefs about morbidity. Smokers and physically inactive were more likely to endorse genetic than behavioral causes of morbidity, whereas obese respondents were more likely to choose overweight over genetic causes of morbidity. Those who endorse genetic factors as the most important cause had more pessimistic outcome beliefs about health behavior changes, but these outcome beliefs became more positive in all causal belief groups during the study period. CONCLUSION: Despite increased public discussion of genomics, the relative proportion of those who endorse genetic factors as the most important cause of morbidity has remained low. However, within this group beliefs about benefits of health behavior changes have become more positive. This could indicate that increase in genomic health information does not lead to more negative appraisals of efficacy of lifestyle changes.

LMNA Mutation c.917T>G (p.L306R) Leads to Deleterious Hyper-Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging.

Mutations in the LMNA gene coding for the nuclear lamina proteins lamin A and its smaller splice form lamin C associate with a heterogeneous group of diseases collectively called laminopathies. Here, we describe a 2-year-old patient with a previously undescribed phenotype including right ventricular cardiomyopathy, progeroid features, and premature death. Sequencing of LMNA revealed a novel heterozygous de novo mutation p.L306R located in the α-helical rod domain of A-type lamins. Fibroblasts from the patient showed reduced proliferation and early premature replicative senescence, as characterized by progressive hyperlobulation of the nuclei, abnormally clustered centromeres, loss of lamin B1, and reorganization of promyelocytic leukemia nuclear bodies. Furthermore, the patient cells were more sensitive to double-strand DNA breaks. Similar structural and phenotypic defects were observed in normal fibroblasts transfected with FLAG-tagged p.L306R lamin A. Correspondingly, in vitro assembly studies revealed that the p.L306R generates a "hyper-assembly" mutant of lamin A that forms extensive fiber arrays under physiological conditions where wild-type lamin A is still largely soluble. In summary, we report a novel LMNA p.L306R mutation that leads to previously undescribed hyper-assembly of lamin A, heavy distortion of nuclear shape and that manifests as right ventricular cardiomyopathy and premature aging.

Points to consider for prioritizing clinical genetic testing services: a European consensus process oriented at accountability for reasonableness.

Given the cost constraints of the European health-care systems, criteria are needed to decide which genetic services to fund from the public budgets, if not all can be covered. To ensure that high-priority services are available equitably within and across the European countries, a shared set of prioritization criteria would be desirable. A decision process following the accountability for reasonableness framework was undertaken, including a multidisciplinary EuroGentest/PPPC-ESHG workshop to develop shared prioritization criteria. Resources are currently too limited to fund all the beneficial genetic testing services available in the next decade. Ethically and economically reflected prioritization criteria are needed. Prioritization should be based on considerations of medical benefit, health need and costs. Medical benefit includes evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient-specific likelihood of being affected by the condition tested for. It may be subject to a finite time window. Health need includes the severity of the condition tested for and its progression at the time of testing. Further discussion and better evidence is needed before clearly defined recommendations can be made or a prioritization algorithm proposed. To our knowledge, this is the first time a clinical society has initiated a decision process about health-care prioritization on a European level, following the principles of accountability for reasonableness. We provide points to consider to stimulate this debate across the EU and to serve as a reference for improving patient management.

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy.

STUDY QUESTION: How has the interface between genetics and assisted reproduction technology (ART) evolved since 2005? SUMMARY ANSWER: The interface between ART and genetics has become more entwined as we increase our understanding about the genetics of infertility and we are able to perform more comprehensive genetic testing. WHAT IS KNOWN ALREADY: In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and ART and published an extended background paper, recommendations and two Editorials. STUDY DESIGN, SIZE, DURATION: An interdisciplinary workshop was held, involving representatives of both professional societies and experts from the European Union Eurogentest2 Coordination Action Project. PARTICIPANTS/MATERIALS, SETTING, METHODS: In March 2012, a group of experts from the European Society of Human Genetics, the European Society of Human Reproduction and Embryology and the EuroGentest2 Coordination Action Project met to discuss developments at the interface between clinical genetics and ART. MAIN RESULTS AND THE ROLE OF CHANCE: As more genetic causes of reproductive failure are now recognized and an increasing number of patients undergo testing of their genome prior to conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and PGD may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from RCTs to substantiate that the technique is both effective and efficient. Whole genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. LIMITATIONS, REASONS FOR CAUTION: The legal landscape regarding assisted reproduction is evolving, but still remains very heterogeneous and often contradictory. The lack of legal harmonization and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe, and beyond. WIDER IMPLICATIONS OF THE FINDINGS: This continually evolving field requires communication between the clinical genetics and IVF teams and patients to ensure that they are fully informed and can make well-considered choices. STUDY FUNDING/COMPETING INTERESTS: Funding was received from ESHRE, ESHG and EuroGentest2 European Union Coordination Action project (FP7 - HEALTH-F4-2010-26146) to support attendance at this meeting.