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Recent advancements in gene-targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long-term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.

In celebration of the 20th anniversary of Nature Reviews Genetics, we asked 12 leading researchers to reflect on the key challenges and opportunities faced by the field of genetics and genomics. Keeping their particular research area in mind, they take stock of the current state of play and emphasize the work that remains to be done over the next few years so that, ultimately, the benefits of genetic and genomic research can be felt by everyone., To celebrate the first 20 years of Nature Reviews Genetics, we asked 12 leading scientists to reflect on the key challenges and opportunities faced by the field of genetics and genomics., The contributors Amy L. McGuire is the Leon Jaworski Professor of Biomedical Ethics and Director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine. She has received numerous teaching awards at Baylor College of Medicine, was recognized by the Texas Executive Women as a Woman on the Move in 2016 and was invited to give a TedMed talk titled “There is No Genome for the Human Spirit” in 2014. In 2020, she was elected as a Hastings Center Fellow. Her research focuses on ethical and policy issues related to emerging technologies, with a particular focus on genomic research, personalized medicine and the clinical integration of novel neurotechnologies. Stacey Gabriel is the Senior Director of the Genomics Platform at the Broad Institute since 2012 and has led platform development, execution and operation since its founding. She is Chair of Institute Scientists and serves on the institute’s executive leadership team. She is widely recognized as a leader in genomic technology and project execution. She has led the Broad’s contributions to numerous flagship projects in human genetics, including the International HapMap Project, the 1000 Genomes Project, The Cancer Genome Atlas, the National Heart, Lung, and Blood Institute’s Exome Sequencing Project and the TOPMed programme. She is Principal Investigator of the Broad’s All of Us (AoU) Genomics Center and serves on the AoU Program Steering Committee. Sarah A. Tishkoff is the David and Lyn Silfen University Associate Professor in Genetics and Biology at the University of Pennsylvania, Philadelphia, USA, and holds appointments in the School of Medicine and the School of Arts and Sciences. She is a member of the US National Academy of Sciences and a recipient of an NIH Pioneer Award, a David and Lucile Packard Career Award, a Burroughs/Wellcome Fund Career Award and an American Society of Human Genetics Curt Stern Award. Her work focuses on genomic variation in Africa, human evolutionary history, the genetic basis of adaptation and phenotypic variation in Africa, and the genetic basis of susceptibility to infectious disease in Africa. Ambroise Wonkam is Professor of Medical Genetics, Director of GeneMAP (Genetic Medicine of African Populations Research Centre) and Deputy Dean Research in the Faculty of Health Sciences, University of Cape Town, South Africa. He has successfully led numerous NIH- and Wellcome Trust-funded projects over the past decade to investigate clinical variability in sickle cell disease, hearing impairment genetics and the return of individual findings in genetic research in Africa. He won the competitive Clinical Genetics Society International Award for 2014 from the British Society of Genetic Medicine. He is president of the African Society of Human Genetics. Aravinda Chakravarti is Director of the Center for Human Genetics and Genomics, the Muriel G. and George W. Singer Professor of Neuroscience and Physiology, and Professor of Medicine at New York University School of Medicine. He is an elected member of the US National Academy of Sciences, the US National Academy of Medicine and the Indian National Science Academy. He has been a key participant in the Human Genome Project, the International HapMap Project and the 1000 Genomes Project. His research attempts to understand the molecular basis of multifactorial disease. He was awarded the 2013 William Allan Award by the American Society of Human Genetics and the 2018 Chen Award by the Human Genome Organization. Eileen E. M. Furlong is Head of the Genome Biology Department at the European Molecular Biology Laboratory (EMBL) and a member of the EMBL Directorate. She is an elected member of the European Molecular Biology Organization (EMBO) and the Academia Europaea, and a European Research Council (ERC) advanced investigator. Her group dissects fundamental principles of how the genome is regulated and how it drives cell fate decisions during embryonic development, including how developmental enhancers are organized and function within the 3D nucleus. Her work combines genetics, (single-cell) genomics, imaging and computational approaches to understand these processes. Her research has advanced the development of genomic methods for use in complex multicellular organisms. Barbara Treutlein is Associate Professor of Quantitative Developmental Biology in the Department of Biosystems Science and Engineering of ETH Zurich in Basel, Switzerland. Her group uses and develops single-cell genomics approaches in combination with stem cell-based 2D and 3D culture systems to study how human organs develop and regenerate and how cell fate is regulated. For her work, Barbara has received multiple awards, including the Friedmund Neumann Prize of the Schering Foundation, the Dr. Susan Lim Award for Outstanding Young Investigator of the International Society of Stem Cell Research and the EMBO Young Investigator Award. Alexander Meissner is a scientific member of the Max Planck Society and currently Managing Director of the Max Planck Institute (MPI) for Molecular Genetics in Berlin, Germany. He heads the Department of Genome Regulation and is a visiting scientist in the Department of Stem Cell and Regenerative Biology at Harvard University. Before his move to the MPI, he was a tenured professor at Harvard University and a senior associate member of the Broad Institute, where he co-directed the epigenomics programme. In 2018, he was elected as an EMBO member. His laboratory uses genomic tools to study developmental and disease biology with a particular focus on epigenetic regulation. Howard Y. Chang is the Virginia and D. K. Ludwig Professor of Cancer Genomics at Stanford University and an investigator at the Howard Hughes Medical Institute. He is a physician–scientist who has focused on deciphering the hidden information in the non-coding genome. His laboratory is best known for studies of long non-coding RNAs in gene regulation and development of new epigenomic technologies. He is an elected member of the US National Academy of Sciences, the US National Academy of Medicine, and the American Academy of Arts and Sciences. Núria López-Bigas is ICREA research Professor at the Institute for Research in Biomedicine and Associate Professor at the University Pompeu Fabra. She obtained an ERC Consolidator Grant in 2015 and was elected as an EMBO member in 2016. Her work has been recognized with the prestigious Banc de Sabadell Award for Research in Biomedicine, the Catalan National Award for Young Research Talent and the Career Development Award from the Human Frontier Science Program. Her research focuses on the identification of cancer driver mutations, genes and pathways across tumour types and in understanding the mutational processes that lead to the accumulation of mutations in cancer cells. Eran Segal is Professor in the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science, heading a multidisciplinary laboratory with extensive experience in machine learning, computational biology and analysis of heterogeneous high-throughput genomic data. His research focuses on the microbiome, nutrition and genetics, and their effect on health and disease and aims to develop personalized medicine based on big data from human cohorts. He has published more than 150 publications and received several awards and honours for his work, including the Overton and the Michael Bruno awards. He was recently elected as an EMBO member and as a member of the Israel Young Academy. Jin-Soo Kim is Director of the Center for Genome Engineering in the Institute for Basic Science in Daejon, South Korea. He has received numerous awards, including the 2017 Asan Award in Medicine, the 2017 Yumin Award in Science and the 2019 Research Excellence Award (Federation of Asian and Oceanian Biochemists and Molecular Biologists). He was featured as one of ten Science Stars of East Asia in Nature (558, 502–510 (2018)) and has been recognized as a highly cited researcher by Clarivate Analytics since 2018. His work focuses on developing tools for genome editing in biomedical research.

In recent decades, genetic genealogy has become popular as a result of direct-to-consumer (DTC) genetic testing. Some DTC genetic testing companies offer genetic relative-finder (GRF) services that compare the DNA of consenting participants to identify genetic relatives among them and provide each participant a list of their relative matches. We surveyed a convenience sample of GRF service participants to understand the prevalence of discoveries and associated experiences. Almost half (46%) of the 23,196 respondents had participated in GRF services only for non-specific reasons that included interest in building family trees and general curiosity. However, most (82%) also learned the identity of at least one genetic relative. Separately, most respondents (61%) reported learning something new about themselves or their relatives, including potentially disruptive information such as that a person they believed to be their biological parent is in fact not or that they have a sibling they had not known about. Respondents generally reported that discovering this new information had a neutral or positive impact on their lives, and most had low regret regarding their decision to participate in GRF services. Yet some reported making life changes as a result of their discoveries. Compared to respondents making other types of discoveries, those who learned that they were donor conceived reported the highest decisional regret and represented the largest proportion reporting net-negative consequences for themselves. Our findings indicate that discoveries from GRF services may be common and that the consequences for individuals, while generally positive, can be far-reaching and complex.

Summary Prior to integration into clinical care, a novel medical innovation is typically assessed in terms of its balance of benefits and risks, often referred to as utility. Members of multidisciplinary research teams may conceptualize and assess utility in different ways, which has implications within the translational genomics community and for the evidence base upon which clinical guidelines groups and healthcare payers make decisions. Ambiguity in the conceptualization of utility in translational genomics research can lead to communication challenges within research teams and to study designs that do not meet stakeholder needs. We seek to address the ambiguity challenge by describing the conceptual understanding of utility and use of the term by scholars in the fields of philosophy, medicine, and the social sciences of decision psychology and health economics. We illustrate applications of each field's orientation to translational genomics research by using examples from the Clinical Sequencing Evidence-Generating Research (CSER) consortium, and we provide recommendations for increasing clarity and cohesion in future research. Given that different understandings of utility will align to a greater or lesser degree with important stakeholders' views, more precise use of the term can help researchers to better integrate multidisciplinary investigations and communicate with stakeholders.

In this Commentary, we argue that in line with the dramatic increase in the collection, storage, and curation of human genomic data for biomedical research, genomic data repositories and consortia have adopted governance frameworks to address the dual objectives of enabling wide access while protecting against possible harms. However, there are ongoing debates in the scientific community about the merits and limitations of different governance frameworks in achieving these twin aims; and indeed, best practices and points for consideration are notably absent when it comes to devising a governance framework for genomic databases. Based on our collective experience of devising and assessing governance frameworks, our Commentary identifies five key functions of “good governance” (or what makes “better governance”) and three areas where trade-offs should be considered when specifying policies within those functions. We apply these functions as a benchmark to describe, as an example, the governance frameworks of six large-scale international genomic projects. ispartof: NATURE GENETICS vol:53 issue:1 pages:2-8 ispartof: location:United States status: published

Although the explosive growth of direct-to-consumer (DTC) genetic testing has moderated, a substantial number of patients are choosing to undergo genetic testing outside the purview of their regular healthcare providers. Further, many industry leaders have been expanding reports to cover many more genes, as well as partnering with employers and others to expand access. This review addresses continuing concerns about DTC genetic testing quality, psychosocial impact, integration with medical practice, effects on the healthcare system, and privacy, as well as emerging concerns about third-party interpretation services and non-health-related uses such as investigative genetic genealogy. It concludes with an examination of two possible futures for DTC genetic testing: merger with traditional modes of healthcare delivery or continuation as a parallel system for patient-driven generation of health-relevant information. Each possibility is associated with distinctive questions related to value and risk.

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

Introduction:Implementation of genome-scale sequencing in clinical care has significant challenges: the technology is highly dimensional with many kinds of potential results, results interpretation and delivery require expertise and coordination across multiple medical specialties, clinical utility may be uncertain, and there may be broader familial or societal implications beyond the individual participant. Transdisciplinary consortia and collaborative team science are well poised to address these challenges. However, understanding the complex web of organizational, institutional, physical, environmental, technologic, and other political and societal factors that influence the effectiveness of consortia is understudied. We describe our experience working in the Clinical Sequencing Evidence-Generating Research (CSER) consortium, a multi-institutional translational genomics consortium.Methods:A key aspect of the CSER consortium was the juxtaposition of site-specific measures with the need to identify consensus measures related to clinical utility and to create a core set of harmonized measures. During this harmonization process, we sought to minimize participant burden, accommodate project-specific choices, and use validated measures that allow data sharing.Results:Identifying platforms to ensure swift communication between teams and management of materials and data were essential to our harmonization efforts. Funding agencies can help consortia by clarifying key study design elements across projects during the proposal preparation phase and by providing a framework for data sharing data across participating projects.Conclusions:In summary, time and resources must be devoted to developing and implementing collaborative practices as preparatory work at the beginning of project timelines to improve the effectiveness of research consortia.

Concern is mounting that innovators are responding to recent changes in patent eligibility by increasingly choosing to protect their discoveries as trade secrets. Due to the clandestine nature of trade secrets, it is impossible to quantify the extent to which innovators actually elect to protect their inventions as trade secrets rather than patents. Nevertheless, interest in each strategy may be gauged through qualitative means. We conducted semi-structured interviews of legal and scientific experts (n = 30) to understand the effect of recent patent eligibility changes on interest in patenting and trade secrecy of genetic innovations. Interview data indicate that secrecy may have increased in strategic appeal relative to patent protection in some areas of genetic innovation, although the actual election of secrecy strategies is often limited as a practical matter. The data also suggest that the burden of navigating the new intellectual property landscape may be falling disproportionately on those who translate gene-based discoveries into clinical applications. Some interviewees expressed concern about the normative implications of secrecy on advancements in and access to genetic medicine. Our findings are potentially relevant to policy proposals intended to restore some of the legal protection that was lost as a result of recent changes to patent eligibility, including amending the federal patent statute and expanding regulatory exclusivities for some genetic technologies.

© 2017 Future Medicine Ltd. Aim: Since whole-genome sequencing (WGS) information can have positive and negative personal utility for individuals, we examined predictors of willingness to pay (WTP) for WGS. Patients & methods: We surveyed two independent populations: adult patients (n = 203) and college seniors (n = 980). Ordinal logistic regression models were used to characterize the relationship between predictors and WTP. Results: Sex, age, education, income, genomic knowledge and knowing someone who had genetic testing or having had genetic testing done personally were associated with significantly higher WTP for WGS. After controlling for income and education, males were willing to pay more for WGS than females. Conclusion: Differences in WTP may impact equity, coverage, affordability and access, and should be anticipated by public dialog about related health policy.

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.

On April 24, 2018, a suspect in California's notorious Golden State Killer cases was arrested after decades of eluding the police. Using a novel forensic approach, investigators identified the suspect by first identifying his relatives using a free, online genetic database populated by individuals researching their family trees. In the wake of the case, media outlets reported privacy concerns with police access to personal genetic data generated by or shared with genealogy services. Recent data from 1,587 survey respondents, however, provide preliminary reason to question whether such concerns have been overstated. Still, limitations on police access to genetic genealogy databases in particular may be desirable for reasons other than current public demand for them.

© 2018 American Society of Human Genetics The Clinical Sequencing Evidence-Generating Research (CSER) consortium, now in its second funding cycle, is investigating the effectiveness of integrating genomic (exome or genome) sequencing into the clinical care of diverse and medically underserved individuals in a variety of healthcare settings and disease states. The consortium comprises a coordinating center, six funded extramural clinical projects, and an ongoing National Human Genome Research Institute (NHGRI) intramural project. Collectively, these projects aim to enroll and sequence over 6,100 participants in four years. At least 60% of participants will be of non-European ancestry or from underserved settings, with the goal of diversifying the populations that are providing an evidence base for genomic medicine. Five of the six clinical projects are enrolling pediatric patients with various phenotypes. One of these five projects is also enrolling couples whose fetus has a structural anomaly, and the sixth project is enrolling adults at risk for hereditary cancer. The ongoing NHGRI intramural project has enrolled primarily healthy adults. Goals of the consortium include assessing the clinical utility of genomic sequencing, exploring medical follow up and cascade testing of relatives, and evaluating patient-provider-laboratory level interactions that influence the use of this technology. The findings from the CSER consortium will offer patients, healthcare systems, and policymakers a clearer understanding of the opportunities and challenges of providing genomic medicine in diverse populations and settings, and contribute evidence toward developing best practices for the delivery of clinically useful and cost-effective genomic sequencing in diverse healthcare settings.

Background Increasing numbers of healthy individuals are undergoing predispositional personal genome sequencing. Here we describe the design and early outcomes of the PeopleSeq Consortium, a multi-cohort collaboration of predispositional genome sequencing projects, which is examining the medical, behavioral, and economic outcomes of returning genomic sequencing information to healthy individuals. Methods Apparently healthy adults who participated in four of the sequencing projects in the Consortium were included. Web-based surveys were administered before and after genomic results disclosure, or in some cases only after results disclosure. Surveys inquired about sociodemographic characteristics, motivations and concerns, behavioral and medical responses to sequencing results, and perceived utility. Results Among 1395 eligible individuals, 658 enrolled in the Consortium when contacted and 543 have completed a survey after receiving their genomic results thus far (mean age 53.0 years, 61.4% male, 91.7% white, 95.5% college graduates). Most participants (98.1%) were motivated to undergo sequencing because of curiosity about their genetic make-up. The most commonly reported concerns prior to pursuing sequencing included how well the results would predict future risk (59.2%) and the complexity of genetic variant interpretation (56.8%), while 47.8% of participants were concerned about the privacy of their genetic information. Half of participants reported discussing their genomic results with a healthcare provider during a median of 8.0 months after receiving the results; 13.5% reported making an additional appointment with a healthcare provider specifically because of their results. Few participants (

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

In the pediatric clinical setting, the parent/guardian will almost always be the authorized representative and designated recipient of clinical and research results, making the issue of to whom results should be returned in the pediatric setting less complex than in adult settings. It is also clear that, in genomic research related to pediatric diseases such as cancer, results may be of considerable clinical, ethical, and personal significance for parents in a number of ways, including a genomic explanation of the origin of their child’s cancer, implications for the genetic testing and medical care of other siblings and of the parents themselves, and reproductive planning with regard to the recurrence risk for future children to have an increased risk of cancer. However, what remains unclear is which results should be disclosed, and under what circumstances, to parents of deceased children.

National and international public–private partnerships, consortia, and government initiatives are underway to collect and share genomic, personal, and healthcare data on a massive scale. Ideally, these efforts will contribute to the creation of a medical information commons (MIC), a comprehensive data resource that is widely available for both research and clinical uses. Stakeholder participation is essential in clarifying goals, deepening understanding of areas of complexity, and addressing long-standing policy concerns such as privacy and security and data ownership. This article describes eight core principles proposed by a diverse group of expert stakeholders to guide the formation of a successful, sustainable MIC. These principles promote formation of an ethically sound, inclusive, participant-centric MIC and provide a framework for advancing the policy response to data-sharing opportunities and challenges.

PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was $5,098 in cardiology settings and $5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = -$1,560, 95% confidence interval -$7,558 to $3,866, p = 0.36; primary care: difference = $681, 95% confidence interval -$884 to $2,171, p = 0.70). Scenario analyses showed the cost reduction of omitting or limiting the types of secondary findings was less than $69 and $182 per patient in cardiology and primary care, respectively.ConclusionShort-term costs of WGS were driven by the costs of sequencing and interpretation rather than downstream health care. Disclosing additional types of secondary findings has a limited cost impact following disclosure.

The ubiquity of DNA sequencing and the advent of medical imaging, electronic health records, and “omics” technologies have produced a deluge of data. Making meaning of those data—creating scientific knowledge and useful clinical information—will vastly exceed the capacity of even the largest institutions. Data must be shared to achieve the promises of genomic science and precision medicine.

© 2017 by the American Academy of Pediatrics. The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genomescale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Thousands of patents have been awarded that claim human gene sequences and their uses, and some have been challenged in court. In a recent high-profile case, Association for Molecular Pathology, et al. v. Myriad Genetics, Inc., et al., the US Supreme Court ruled that genes are natural occurring substances and therefore not patentable through 'composition of matter' claims. The consequences of this ruling will extend well beyond ending Myriad's monopoly over BRCA testing and may affect similar monopolies of other commercial laboratories for tests involving other genes. It could also simplify intellectual property issues surrounding genome-wide clinical sequencing, which can generate results for genes covered by intellectual property. Non-invasive prenatal testing (NIPT) for common aneuploidies using cell-free fetal (cff) DNA in maternal blood is currently offered through commercial laboratories and is also the subject of ongoing patent litigation. The recent Supreme Court decision in the Myriad case has already been invoked by a lower district court in NIPT litigation and resulted in invalidation of primary claims in a patent on currently marketed cffDNA-based testing for chromosomal aneuploidies.

Genomic researchers increasingly are faced with difficult decisions about whether, under what circumstances, and how to return research results and significant incidental findings to study participants. Many have argued that there is an ethical—maybe even a legal—obligation to disclose significant findings under some circumstances. At the international level, over the last decade there has begun to emerge a clear legal obligation to return significant findings discovered during the course of research. However, there is no explicit legal duty to disclose in the United States. This creates legal uncertainty that may lead to unmanaged variation in practice and poor quality care. This article discusses liability risks associated with the disclosure of significant research findings for investigators in the United States.

Prospects have never seemed better for a truly global approach to science to improve human health, with leaders of national initiatives laying out their vision of a worldwide network of related projects. An extensive literature addresses obstacles to global genomic data sharing, yet a series of public polls suggests that the scientific community may be overlooking a significant barrier: potential public resistance to data sharing across national borders. In several large United States surveys, university researchers in other countries were deemed the least acceptable group of data users, and a just-completed US survey found a marked increase in privacy and security concerns related to data access by non-US researchers. Furthermore, diminished support for sharing beyond national borders is not unique to the US, although the limited data from outside the US suggest variation across countries as well as demographic groups. Possible sources of resistance include apprehension about privacy and security protections. Strategies for building public support include making the affirmative case for global data sharing, addressing privacy, security, and other legitimate concerns, and investigating public concerns in greater depth.

The advent of whole-exome next-generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½-year old female patient with a 2-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies.

In 2007, the National Human Genome Research Institute (NHGRI) established the Electronic MEdical Records and GEnomics (eMERGE) Consortium (www.gwas.net) to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic medical record (EMR) systems for large-scale, high-throughput genetic research. One of the major ethical and administrative challenges for the eMERGE Consortium has been complying with existing data-sharing policies. This paper discusses the challenges of sharing genomic data linked to health information in the electronic medical record (EMR) and explores the issues as they relate to sharing both within a large consortium and in compliance with the National Institutes of Health (NIH) data-sharing policy. We use the eMERGE Consortium experience to explore data-sharing challenges from the perspective of multiple stakeholders (i.e., research participants, investigators, and research institutions), provide recommendations for researchers and institutions, and call for clearer guidance from the NIH regarding ethical implementation of its data-sharing policy.

In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago. Although unable to reach consensus on a number of issues, the working group produced 5 recommendations. The working group offers 2 recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to institutional review boards, investigators, research institutions, and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.

There are several features of genetic and genomic research that challenge established norms of informed consent. In this paper, we discuss these challenges, explore specific elements of informed consent for genetic and genomic research conducted in the United States, and consider alternative consent models that have been proposed. All of these models attempt to balance the obligation to respect and protect research participants with the larger social interest in advancing beneficial research as quickly as possible.

During the last decade, the field of human genome research has gone through a phase of rapid discovery that has provided scientists and physicians with a wide variety of research tools that are applicable to important medical issues. We describe a true case of familial Huntington disease (HD) in which we modified personal details to protect patient's privacy, where the proband at risk preferred not to know his disease status but wanted to know the status in his unborn child. Once we found the father to be negative, the case raised an important ethical question regarding the management of this as well as future pregnancies. This article discusses the arguments for and against the right not to know of one's carrier status, as well as professional obligations in the context of withholding unwanted information that may have direct implications not only for the patient himself but also for other family members. HD has served as a model for many other adult onset genetic diseases in terms of carrier testing guidelines. Hence, we feel it is time to revisit the issue of prenatal testing for HD and consider updating the current recommendations regarding the patient's right to "genetic ignorance", or the right not to know genetic information.

Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state-mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cutoff into the normal range. To determine whether the infant was biotinidase-deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BTD, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial BTD and informed this novel splice site's reclassification, emphasizing the importance of combining iterative genetic and phenotypic evaluations.

BACKGROUND Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease. METHODS We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. RESULTS We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome. CONCLUSIONS As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.

The ability to generate personalized genomic information for large numbers of people is rapidly becoming a reality. Four experts provide their opinions on how useful this information is likely to be and how it should best be put to use.

Advances in genomic technology make possible the large-scale collection of genomic data for research purposes. Many international initiatives seek to collect genomic data on large populations, often relying on existing collections to populate their databases. As these efforts progress, the debate over whether or not to return individual genetic research results to study participants remains an area of much contention. Some recommend returning results to participants only if the issue was addressed in the original study consent form. Much of the data being used in current studies, however, may have been derived from biospecimens collected years ago with consent documents that did not anticipate the possibility of returning individual level genomic results. We conducted an analysis of informed consent documents from published genome-wide association studies (GWAS) (n=40) to explore whether future research use of biospecimens or data is anticipated, and if return of results is addressed and how it is described to better understand participants’ expectations for future disclosure. The majority (70%) of the GWAS consent documents we analyzed either stated explicitly that individual genomic results would not be returned or were silent on the issue. This has implications for how researchers and members of Research Ethics Committees manage the return of results from sequencing studies using legacy samples and data.

Although the integration of whole genome sequencing (WGS) into standard medical practice is rapidly becoming feasible, physicians may be unprepared to use it. Primary care physicians (PCPs) and cardiologists enrolled in a randomized clinical trial of WGS received genomics education before completing semi-structured interviews. Themes about preparedness were identified in transcripts through team-based consensus-coding. Data from 11 PCPs and 9 cardiologists suggested that physicians enrolled in the trial primarily to prepare themselves for widespread use of WGS in the future. PCPs were concerned about their general genomic knowledge, while cardiologists were concerned about how to interpret specific types of results and secondary findings. Both cohorts anticipated preparing extensively before disclosing results to patients by using educational resources with which they were already familiar, and both cohorts anticipated making referrals to genetics specialists as needed. A lack of laboratory guidance, time pressures, and a lack of standards contributed to feeling unprepared. Physicians had specialty-specific concerns about their preparedness to use WGS. Findings identify specific policy changes that could help physicians feel more prepared, and highlight how providers of all types will need to become familiar with interpreting WGS results.

The circumstances surrounding the creation of the HeLa cell line are now well known. The best-selling book by Rebecca Skloot, The Immortal Life of Henrietta Lacks ([Skloot 2010][1]), detailed both the creation of the cell line and the associated ethical and social controversies. The Skloot book

Few areas of research have received as much attention from the popular press as stem cells. And it is no wonder. Stem cell research is extraordinarily promising, with the potential to produce groundbreaking therapies for a range of ailments. In addition, it has generated an exceptional amount of public policy controversy, attracting attention from presidents, prime ministers, legislators, and religious leaders throughout the world. Combined, the representations of the promise and perils of this area of scientific inquiry have made stem cell research nothing short of a pop culture phenomenon. But many have speculated that this hype can be a less than constructive force,1 contributing to numerous science policy challenges—including the growing market for unproven stem cell therapies.

Genet Med (2013) 15, 565–574 doi:10.1038/gim.2013.73 In the published version of this paper, on page 567, on the 16th line in the last paragraph of the left column, the abbreviation of Expected Pathogenic is incorrect. The correct sentence should read, “For the purposes of these recommendations, variants fitting these descriptions were labeled as Known Pathogenic (KP) and Expected Pathogenic (EP), respectively.

Background Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures. Methods A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients. Results Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures. Conclusions An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0069-3) contains supplementary material, which is available to authorized users.

The current emphasis on broad sharing of human genomic data generated in research in order to maximize utility and public benefit is a significant legacy of the Human Genome Project. Concerns about privacy and discrimination have led to policy responses that restrict access to genomic data as the means for protecting research participants. Our research and experience show, however, that a considerable number of research participants agree to open access sharing of their genomic data when given the choice. General policies that limit access to all genomic data fail to respect the autonomy of these participants and, at the same time, unnecessarily limit the utility of the data. We advocate instead a more balanced approach that allows for individual choice and encourages informed decision making, while protecting against the misuse of genomic data through enhanced legislation.

The current model for conducting genome-wide association studies (GWAS) is primarily phenotype-driven. In this “top-down” approach, the model is the case-control study, where participants are enrolled based on the presence or absence of a clinical phenotype, for example, cardiovascular disease or breast cancer (Pennisi 2007; Wellcome Trust Case Control Consortium 2007). The International HapMap Project has identified a large number of single nucleotide polymorphisms (SNPs) in the human population that enable investigators to genotype subjects for these various polymorphisms and determine associations with a phenotype of interest (Fig. 1A) (International HapMap Consortium et al. 2007).

Next-generation sequencing (NGS) is commonly used for researching the causes of genetic disorders. However, its usefulness in clinical practice for medical diagnosis is in early development. In this report, we demonstrate the value of NGS for genetic risk assessment and evaluate the limitations and barriers for the adoption of this technology into medical practice. We performed whole exome sequencing (WES) on 81 volunteers, and for each volunteer, we requested personal medical histories, constructed a three-generation pedigree, and required their participation in a comprehensive educational program. We limited our clinical reporting to disease risks based on only rare damaging mutations and known pathogenic variations in genes previously reported to be associated with human disorders. We identified 271 recessive risk alleles (214 genes), 126 dominant risk alleles (101 genes), and 3 X-recessive risk alleles (3 genes). We linked personal disease histories with causative disease genes in 18 volunteers. Furthermore, by incorporating family histories into our genetic analyses, we identified an additional five heritable diseases. Traditional genetic counseling and disease education were provided in verbal and written reports to all volunteers. Our report demonstrates that when genome results are carefully interpreted and integrated with an individual’s medical records and pedigree data, NGS is a valuable diagnostic tool for genetic disease risk.

Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained. Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed. In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition. Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient. Genet Med 2013:15(1):45–54