Holly Tabor, PhD, is Associate Professor of Medicine at Stanford University. She is the Associate Director for Clinical Ethics and Education for the Stanford Center for Biomedical Ethics (SCBE) and is Co-Chair of the Ethics Committees at Stanford Hospital and Lucile Packard Children’s Hospital. Her research focuses on ethical issues in genetics and genomics, specifically return of results and translation for exome and whole genome sequencing. She received her PhD in Epidemiology from Stanford in 2002, and then was a Senior Scientist at the Stanford Human Genome Center. From 2005-2008 she was one of the first postdoctoral fellows at CIRGE/SCBE. Prior to her work at SCBE she spent eight years at the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Research Institute and at the University of Washington.
Co-Chair, Lucile Packard Children's Hospital Ethics Committee (2018 - Present)
Co-Chair, Stanford Hospital Clinical Ethics Committee (2018 - Present)
Member, Stanford Hospital Clinical Ethics Committee (2016 - 2018)
Member, Lucile Packard Children's Hospital Ethics Committee (2016 - 2018)
Postdoc, Stanford University School of Medicine, Bioethics (2008)
PhD, Stanford University School of Medicine, Epidemiology (Minor Genetics) (2002)
AB, Harvard University, History and Science (1994)
Current Research and Scholarly Interests
My research focuses on ethical issues in genetics and genomics, specifically return of results and translation for exome and whole genome sequencing and translation of genomic sequencing into the clinical setting. I also conduct research on ethical issues in clinical care and research for patients and families with autism and other developmental and cognitive disabilities.
Postdoctoral Faculty Sponsor
Patient and family social media use surrounding a novel treatment for a rare genetic disease: a qualitative interview study.
Genetics in medicine : official journal of the American College of Medical Genetics
PURPOSE: Advances in gene therapy and precision medicine have led to a growing number of novel treatments for rare genetic diseases. Patients/families may lack access to up-to-date, accurate, and relevant information about these treatments. Social media offers one potentially important resource for these communities. Our goal was to understand how patients/families with spinal muscular atrophy (SMA)-a rare genetic condition-used social media to share, consume, and evaluate information about the novel treatment nusinersen (Spinraza) following the drug's approval.METHODS: We conducted qualitative, semistructured interviews with 20 SMA patients or parents of patients, deriving themes and subthemes through content and thematic network analysis. Participants also completed a demographic survey.RESULTS: Participants described leveraging social media to learn about nusinersen treatment, make informed treatment decisions, and advocate for/access treatment. They also described critically evaluating the trustworthiness of nusinersen-related information on social media and the privacy risks of social media use.CONCLUSION: Patients/families used social media to navigate the new and dynamic landscape of nusinersen treatment for SMA, while attempting to mitigate misinformation and privacy risks. As new treatments become available, providers and patients/families may benefit from proactively discussing social media use, so as to maximize important benefits while minimizing risks.
View details for DOI 10.1038/s41436-020-0890-6
View details for PubMedID 32601388
De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
American journal of human genetics
EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
View details for DOI 10.1016/j.ajhg.2020.02.016
View details for PubMedID 32197074
Ventilator Triage Policies During the COVID-19 Pandemic at U.S. Hospitals Associated With Members of the Association of Bioethics Program Directors.
Annals of internal medicine
The coronavirus disease 2019 pandemic has or threatens to overwhelm health care systems. Many institutions are developing ventilator triage policies.To characterize the development of ventilator triage policies and compare policy content.Survey and mixed-methods content analysis.North American hospitals associated with members of the Association of Bioethics Program Directors.Program directors.Characteristics of institutions and policies, including triage criteria and triage committee membership.Sixty-seven program directors responded (response rate, 91.8%); 36 (53.7%) hospitals did not yet have a policy, and 7 (10.4%) hospitals' policies could not be shared. The 29 institutions providing policies were relatively evenly distributed among the 4 U.S. geographic regions (range, 5 to 9 policies per region). Among the 26 unique policies analyzed, 3 (11.3%) were produced by state health departments. The most frequently cited triage criteria were benefit (25 policies [96.2%]), need (14 [53.8%]), age (13 [50.0%]), conservation of resources (10 [38.5%]), and lottery (9 [34.6%]). Twenty-one (80.8%) policies use scoring systems, and 20 of these (95.2%) use a version of the Sequential Organ Failure Assessment score. Among the policies that specify the triage team's composition (23 [88.5%]), all require or recommend a physician member, 20 (87.0%) a nurse, 16 (69.6%) an ethicist, 8 (34.8%) a chaplain, and 8 (34.8%) a respiratory therapist. Thirteen (50.0% of all policies) require or recommend those making triage decisions not be involved in direct patient care, but only 2 (7.7%) require that their decisions be blinded to ethically irrelevant considerations.The results may not be generalizable to institutions without academic bioethics programs.Over one half of respondents did not have ventilator triage policies. Policies have substantial heterogeneity, and many omit guidance on fair implementation.
View details for DOI 10.7326/M20-1738
View details for PubMedID 32330224
- Civic Engagement, Autism and Deliberative Democracy: Prioritizing the Inclusion of Marginalized Perspectives. The American journal of bioethics : AJOB 2020; 20 (4): 41–43
Rethinking the "open future" argument against predictive genetic testing of children
GENETICS IN MEDICINE
2019; 21 (10): 2190–98
Professional consensus has traditionally discouraged predictive genetic testing when no childhood interventions can reduce future morbidity or mortality. However, advances in genome sequencing and accumulating evidence that children and families cope adequately with predictive genetic information have weakened this consensus. The primary argument remaining against testing appeals to children's "right to an open future." It claims that the autonomy of the future adult is violated when others make an irreversible choice to obtain or disclose predictive genetic information during childhood. We evaluate this argument and conclude that children's interest in an open future should not be understood as a right. Rather an open future is one significant interest to weigh against other important interests when evaluating decisions. Thus, predictive genetic testing is ethically permissible in principle, as long as the interests promoted outweigh potential harms. We conclude by offering an expanded model of children's interests that might be considered in such circumstances, and present two case analyses to illustrate how this framework better guides decisions about predictive genetic testing in pediatrics.
View details for DOI 10.1038/s41436-019-0483-4
View details for Web of Science ID 000488530100006
View details for PubMedID 30894702
View details for PubMedCentralID PMC6754817
De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.
American journal of human genetics
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
View details for DOI 10.1016/j.ajhg.2019.06.014
View details for PubMedID 31327508
- "Before Facebook and before social media...we did not know anybody else that had this": parent perspectives on internet and social media use during the pediatric clinical genetic testing process JOURNAL OF COMMUNITY GENETICS 2019; 10 (3): 375–83
Assessing genetic counselors' experiences with physician aid-in-dying and practice implications.
Journal of genetic counseling
Physician aid-in-dying (PAD) is now legalized in more than half a dozen states across the United States yet remains controversial among health care providers and the general public. Previous studies have described physicians' and nurses' experiences with and attitudes about PAD; however, there is no data about PAD in the context of genetic counseling. This study explores genetic counselors' experiences, understanding, training, and perspectives about PAD. Fifteen participants were recruited to complete semistructured telephone interviews. Five participants had received patient inquiries about PAD. Most participants (n=10) did not feel prepared to discuss PAD with patients and felt that they did not have adequate knowledge to answer patient questions about the practice. Participants described how the unique training, skills, and experiences of genetic counselors could be beneficial for discussing PAD with patients, in comparison to other providers. All participants supported training for genetic counselors about PAD, with many suggesting integration with education about palliative care and end-of-life planning. This is the first study to investigate PAD in the context of genetic counseling. Genetic counselors have had patients ask questions about PAD, want education and access to resources about PAD, and believe they can provide important support and guidance to patients considering PAD in some genetic counseling contexts.
View details for PubMedID 30688387
- Consent insufficient for data release. Science (New York, N.Y.) 2019; 364 (6439): 445–46
High-Throughput Sequencing in Respiratory, Critical Care, and Sleep Medicine Research An Official American Thoracic Society Workshop Report
ANNALS OF THE AMERICAN THORACIC SOCIETY
2019; 16 (1): 1–16
High-throughput, "next-generation" sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.
View details for DOI 10.1513/AnnalsATS.201810-716WS
View details for Web of Science ID 000454507300001
View details for PubMedID 30592451
Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy.
Journal of neuromuscular diseases
BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment.OBJECTIVE: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition.METHODS: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment.RESULTS: Thirteen people were interviewed: ten adults with SMA (ages 27- 48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups.CONCLUSIONS: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.
View details for PubMedID 30594933
"Before Facebook and before social mediawe did not know anybody else that had this": parent perspectives on internet and social media use during the pediatric clinical genetic testing process.
Journal of community genetics
Parents of children who undergo clinical genetic testing have significant informational and emotional support needs at different stages of the testing process. We analyzed parent views about use of both the internet and social media to help meet these needs. We interviewed 20 parents of children who underwent clinical genetic testing and analyzed transcripts to identify themes related to internet and social media use. Parents described using the internet to search for information at three stages of the genetic testing process: before testing, pending results return, and after results return. Each stage corresponded to different information vacuums and needs. Parents also described using condition-specific Facebook groups to learn more about their child's condition and to find support networks of families with similar experiences in ways that were challenging using non-social media approaches. Both the internet and social media play important roles in meeting informational and support needs in pediatric genetic testing, especially for rare conditions. Providers should consider engaging parents at different stages of the testing process about their use of the internet and social media, and consider directing them to vetted sites and groups as part of shared decision making and to improve satisfaction and outcomes.
View details for PubMedID 30569339
What Precision Medicine Can Learn from Rare Genetic Disease Research and Translation.
AMA journal of ethics
2018; 20 (9): E834–840
The goal of this article is to examine the intersections of precision health and rare diseases. Specifically, we propose 3 lessons from the last decade of applying genomics to rare diseases: (1) precision can end one odyssey and start another; (2) precise interventions can exacerbate health disparities and create other ethical dilemmas; and (3) democratization of data will transform research and translation. By studying experiences of patients with rare diseases, researchers, clinicians, and policymakers can anticipate similar challenges in precision medicine and hopefully mitigate potential harms or injustices.
View details for PubMedID 30242814
Approaches to carrier testing and results disclosure in translational genomics research: The clinical sequencing exploratory research consortium experience.
Molecular genetics & genomic medicine
BACKGROUND: Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed.METHODS: Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects.RESULTS: The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results.CONCLUSION: Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.
View details for PubMedID 30133189
Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy.
2018; 172 (2): 188–92
The US Food and Drug Administration's December 2016 approval of nusinersen for the treatment of patients with all subtypes of spinal muscular atrophy ushered in a new era for patients with spinal muscular atrophy, their families, and all those involved in their care. The extreme cost of the medication and the complicated logistical requirements for administering nusinersen via lumbar puncture have created practical challenges that raise important ethical considerations. We discuss 6 challenges faced at the institutional level in the United States: cost, limited evidence, informed consent, treatment allocation, fair distribution of responsibilities, and transparency with stakeholders. These challenges must be understood to ensure that patients with spinal muscular atrophy benefit from treatment, are protected from harm, and are treated fairly.
View details for PubMedID 29228163
Pathways from autism spectrum disorder diagnosis to genetic testing.
Genetics in medicine : official journal of the American College of Medical Genetics
PurposeThis study examined challenges faced by families and health providers related to genetic testing for autism spectrum disorder (ASD).MethodsThis qualitative study of 14 parents and 15 health providers identified an unstandardized three-step process for families who pursue ASD genetic testing.ResultsStep 1 is the clinical diagnosis of ASD, confirmed by providers practicing alone or in a team. Step 2 is the offer of genetic testing to find an etiology. For those offered testing, step 3 involves the parents' decision whether to pursue testing. Despite professional guidelines and recommendations, interviews describe considerable variability in approaches to genetic testing for ASD, a lack of consensus among providers, and questions about clinical utility. Many families in our study were unaware of the option for genetic testing; testing decisions by parents appear to be influenced by both provider recommendations and insurance coverage.ConclusionConsideration of genetic testing for ASD should take into account different views about the clinical utility of testing and variability in insurance coverage. Ideally, policy makers from the range of clinical specialties involved in ASD care should revisit policies to clarify the purpose of genetic testing for ASD and promote consensus about its appropriate use.GENETICS in MEDICINE advance online publication, 19 October 2017. doi:10.1038/gim.2017.166.
View details for PubMedID 29048417
My46: a Web-based tool for self-guided management of genomic test results in research and clinical settings.
Genetics in medicine
A major challenge to implementing precision medicine is the need for an efficient and cost-effective strategy for returning individual genomic test results that is easily scalable and can be incorporated into multiple models of clinical practice. My46 is a Web-based tool for managing the return of genetic results that was designed and developed to support a wide range of approaches to disclosing results, ranging from traditional face-to-face disclosure to self-guided models. My46 has five key functions: set and modify results-return preferences, return results, educate, manage the return of results, and assess the return of results. These key functions are supported by six distinct modules and a suite of features that enhance the user experience, ease site navigation, facilitate knowledge sharing, and enable results-return tracking. My46 is a potentially effective solution for returning results and supports current trends toward shared decision making between patients and providers and patient-driven health management.Genet Med advance online publication 15 September 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.133.
View details for DOI 10.1038/gim.2016.133
View details for PubMedID 27632689
Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine
AMERICAN JOURNAL OF HUMAN GENETICS
2016; 98 (6): 1051–66
Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.
View details for PubMedID 27181682
View details for PubMedCentralID PMC4908179
Use of metaphors about exome and whole genome sequencing.
American journal of medical genetics. Part A
2016; 170A (5): 1127-1133
Clinical and research uses of exome and whole genome sequencing (ES/WGS) are growing rapidly. An enhanced understanding of how individuals conceptualize and communicate about sequencing results is needed to ensure effective, mutual exchange of information between care providers and patients and between researchers and participants. Focus groups and interviews participants were recruited to discuss their attitudes and preferences for receiving hypothetical results from ES/WGS. African Americans were intentionally oversampled. We qualitatively analyzed participants' speech to identify unsolicited metaphorical language pertaining to genes and health, and grouped these occurrences into metaphorical concepts. Participants compared genetic information to physical objects including tools, weapons, contents of boxes, and formal documents or reports. These metaphorical concepts centered on several key themes, including locus of control; containment versus release of information; and desirability, usability, interpretability, and ownership of genetic results. Metaphorical language is often used intentionally or unintentionally in discussions about receiving results from ES/WGS in both clinical and research settings. Awareness of the use of metaphorical language and attention to its varied meanings facilitates effective communication about return of ES/WGS results. In turn, both should foster shared and informed decision-making and improve the translation of genetic information by clinicians and researchers.
View details for DOI 10.1002/ajmg.a.37571
View details for PubMedID 26822973
- When Participants in Genomic Research Grow Up: Contact and Consent at the Age of Majority JOURNAL OF PEDIATRICS 2016; 168: 226-+
Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.
Genetics in medicine : official journal of the American College of Medical Genetics
2016; 18 (8): 788–95
The pace of Mendelian gene discovery is slowed by the "n-of-1 problem"-the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers.Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/#/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.Genet Med 18 8, 788-795.
View details for PubMedID 26656649
View details for PubMedCentralID PMC4902791
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.
American journal of human genetics
2015; 97 (2): 199-215
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.
View details for DOI 10.1016/j.ajhg.2015.06.009
View details for PubMedID 26166479
View details for PubMedCentralID PMC4573249
Actionable exomic incidental findings in 6503 participants: challenges of variant classification
2015; 25 (3): 305-315
Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
View details for DOI 10.1101/gr.183483.114
View details for Web of Science ID 000350526700001
View details for PubMedID 25637381
View details for PubMedCentralID PMC4352885
"We Don't Know Her History, Her Background": Adoptive Parents' Perspectives on Whole Genome Sequencing Results
JOURNAL OF GENETIC COUNSELING
2015; 24 (1): 67-77
Exome sequencing and whole genome sequencing (ES/WGS) can provide parents with a wide range of genetic information about their children, and adoptive parents may have unique issues to consider regarding possible access to this information. The few papers published on adoption and genetics have focused on targeted genetic testing of children in the pre-adoption context. There are no data on adoptive parents' perspectives about pediatric ES/WGS, including their preferences about different kinds of results, and the potential benefits and risks of receiving results. To explore these issues, we conducted four exploratory focus groups with adoptive parents (N = 26). The majority lacked information about their children's biological family health history and ancestry, and many viewed WGS results as a way to fill in these gaps in knowledge. Some expressed concerns about protecting their children's future privacy and autonomy, but at the same time stated that WGS results could possibly help them be proactive about their children's health. A few parents expressed concerns about the risks of WGS in a pre-adoption context, specifically about decreasing a child's chance of adoption. These results suggest that issues surrounding genetic information in the post-adoption and ES/WGS contexts need to be considered, as well as concerns about risks in the pre-adoption context. A critical challenge for ES/WGS in the context of adoption will be balancing the right to know different kinds of genetic information with the right not to know. Specific guidance for geneticists and genetic counselors may be needed to maximize benefits of WGS while minimizing harms and prohibiting misuse of the information in the adoption process.
View details for DOI 10.1007/s10897-014-9738-z
View details for Web of Science ID 000348131000008
View details for PubMedID 25011977
View details for PubMedCentralID PMC4291307
Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.
2015; 11 (6): e1005273
Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.
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Single-nucleotide polymorphism arrays and unexpected consanguinity: considerations for clinicians when returning results to families.
Genetics in medicine : official journal of the American College of Medical Genetics
2015; 17 (5): 400–404
The broad use of single-nucleotide polymorphism microarrays has increased identification of unexpected consanguinity. Therefore, guidelines to address reporting of consanguinity have been published for clinical laboratories. Because no such guidelines for clinicians exist, we describe a case and present recommendations for clinicians to disclose unexpected consanguinity to families.In a boy with multiple endocrine abnormalities and structural birth defects, single-nucleotide polymorphism array analysis revealed ~23% autosomal homozygosity suggestive of a first-degree parental relationship. We assembled an interdisciplinary health-care team, planned the most appropriate way to discuss results of the single-nucleotide polymorphism array with the adult mother, including the possibility of multiple autosomal recessive disorders in her child, and finally met with her as a team.From these discussions, we developed four major considerations for clinicians returning results of unexpected consanguinity, all guided by the child's best interests: (i) ethical and legal obligations for reporting possible abuse, (ii) preservation of the clinical relationship, (iii) attention to justice and psychosocial challenges, and (iv) utilization of the single-nucleotide polymorphism array results to guide further testing.As single-nucleotide polymorphism arrays become a common clinical diagnostic tool, clinicians can use this framework to return results of unexpected consanguinity to families in a supportive and productive manner.
View details for PubMedID 25232848
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De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.
American journal of human genetics
2015; 96 (3): 462–73
Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).
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Pathogenic Variants for Mendelian and Complex Traits in Exomes of 6,517 European and African Americans: Implications for the Return of Incidental Results
AMERICAN JOURNAL OF HUMAN GENETICS
2014; 95 (2): 183-193
Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results.
View details for DOI 10.1016/j.ajhg.2014.07.006
View details for Web of Science ID 000340076000005
View details for PubMedID 25087612
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Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset
HUMAN MOLECULAR GENETICS
2014; 23 (8): 1957-1963
The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
View details for DOI 10.1093/hmg/ddt588
View details for Web of Science ID 000333269400001
Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
American journal of human genetics
2014; 94 (2): 233-245
Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
View details for DOI 10.1016/j.ajhg.2014.01.010
View details for PubMedID 24507775
Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing.
American journal of human genetics
2014; 95 (1): 77–84
Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85%), healthy adults (75%), and the parents of a child with a medical condition (74%). The majority thought that incidental results about adult-onset conditions (62%) and carrier status (62%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81%) thought that individual preferences should guide return. Genetics professionals' perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.
View details for PubMedID 24975944
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Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.
American journal of human genetics
2014; 94 (5): 734–44
Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
View details for PubMedID 24726473
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Parent perspectives on pediatric genetic research and implications for genotype-driven research recruitment.
Journal of empirical research on human research ethics : JERHRE
2011; 6 (4): 41–52
As genetic research is increasingly conducted in children, it is important to understand how parents make decisions about enrolling their children and what they think about receiving their children's genetic research results. We conducted semi-structured phone interviews with 23 parents of children enrolled in genetic studies of autism or diabetes. Qualitative thematic analysis focused on two important components of genetic research and genotype-driven recruitment: participation in genetic research and return of results. Our findings suggest that parents' preferences and perspectives may be specific to their child's disease and the needs of the family as a whole. Assessing the expectations of target research populations will be beneficial for developing best practices for pediatric genetic research, return of results, and genotype-driven recruitment.
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- Challenges in the use of direct-to-consumer personal genome testing in children. The American journal of bioethics : AJOB 2009; 9 (6-7): 32–34
Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research
GENETICS IN MEDICINE
2007; 9 (9): 626-631
As with many new diagnostic technologies, the recent rapid emergence of array comparative genome hybridization in clinical genetics provides the power to observe new biological phenomena before their clinical significance is well understood. This raises ethical issues for clinicians when applying the technologies. However, at this early stage of research and development on array comparative genome hybridization, the ethical implications of the conduct of research, as well as how research findings are presented and interpreted, should also be considered by the research, clinical, and ethics communities. These considerations are especially important in the use of array comparative genome hybridization to study complex and common traits. We examined recent publications on autism as an example of the application of array comparative genome hybridization to a complex phenotype. Our goal was to identify points to consider for researchers, clinicians, and patients/families to ensure responsible and ethical design, presentation, and interpretation of these kinds of studies.
View details for DOI 10.1097/GIM.0b013e3181485688
View details for Web of Science ID 000249640800010
View details for PubMedID 17873651
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Candidate-gene approaches for studying complex genetic traits: practical considerations
NATURE REVIEWS GENETICS
2002; 3 (5): 391-A396
Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.
View details for DOI 10.1038/nrg796
View details for Web of Science ID 000175350000016
View details for PubMedID 11988764