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Tuesday, October 22

4:30 PM–5:00 PM

SESSION 1 – ASHG Presidential Address: Just Another President's Speech (BUT It's All About You)

Hall B2, Level 0 (Lower Level), Convention Center

Although our society turned 65 this year it is far from ready for retirement. Our members have led the way as changes in knowledge, technology, policy and education have challenged our mission over the last seven decades. Genetics has never been more central than it is today to the national and international conversations surrounding science and its application in health, law and teaching. But we must ever focus our commitment to being a part of the solution to the changes that confront us. Having an engaged and active membership who create a strategic vision for our future can ensure that we increase in relevance and utility for ASHG in particular and for advancing the good of society in general.

 

 

Presenter: Jeff Murray, University of Iowa


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 3 – A Renaissance in Gene Therapy: New Tools and Clinical Trials

Room TBD, Convention Center

Moderators: Stephen Kaler, NICHD/NIH
  Luk H. Vandenberghe, Harvard Med. Sch.

This session will focus on expanding knowledge and experience in the field of therapeutic gene transfer, with a focus on monogenetic disorders. Advances in somatic gene transfer have led to a renaissance in the field, in large part due to recent success in early clinical trials for hemophilia and inherited blinding diseases. This session will provide an update on recent improvements in the development of adeno-associated viral and lentiviral vector systems. Speakers will discuss preclinical and clinical advances that these novel technologies have enabled. Emerging data on the clinical application of viral gene therapy, as well as the contribution of this approach to understanding of disease mechanism and pathophysiology will be highlighted.

 

8:00 AM   Adeno-associated viral vectors for gene therapy: Virus, vector, nanoparticle. L. H. Vandenberghe. Harvard Med. Sch.

8:30 AM   Gene therapy for metabolic CNS disorders. R. G. Crystal. Weill Cornell Med. Col.

9:00 AM   Brain-directed AAV gene therapy. S. Kaler. NICHD/NIH.

9:30 AM   Lentiviral-mediated gene therapy for human disease: Extensive genetic engineering of hematopoiesis with therapeutic benefit in metachromatic leukodystrophy patients after lentiviral hematopoietic stem cell gene therapy. L. Naldini. San Raffaele Telethon Inst. for Gene Therapy, Milan.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 4 – DNA Damage Response Network Defects and Cancer Predisposition: Where One Plus One Does Not Equal Two

Room TBD, Convention Center

Moderators: Marc Tischkowitz, Univ. of Cambridge
  William D. Foulkes, McGill Univ.

Ataxia-telangiectasia (A-T) and Fanconi Anemia (FA) are important DNA damage response network syndromes whose genes exhibit different clinical phenotypes in the mono-allelic and bi-allelic mutated state. In 2002, D’Andrea and colleagues made the pivotal discovery that biallelic mutations in FANCD1/BRCA2 are a cause of FA. Since then two other genes (FANCJ/BRIP1, FANCN/PALB2) have been shown to cause FA and hereditary breast cancer in a similar manner while a fourth gene, RAD51C/FANCO causes an FA-like phenotype and hereditary ovarian cancer. Genes in the FA/BRCA pathway predispose to a number of other malignancies including prostate cancer (BRCA2), pancreatic cancer (BRCA2&PALB2) and pediatric brain tumors, Wilms tumors, leukemias (all seen in FA). Interestingly, bi-allelic mutations in a fifth gene, BRCA1 (a FANCJ/BRIP1 binding partner), have recently been shown to cause an inherited ovarian cancer syndrome distinct from FA. The proteins encoded by these genes act downstream of the core FA complex and study of their interactions has given insight into key mechanisms underlying cancer predisposition. However, many questions remain e.g. why is FA due to biallelic BRCA2/PALB2 mutations more severe compared to other FA complementation groups? How can we explain the different cancer spectrum and penetrance caused by mono-allelic mutations in these genes? What can we learn about the role of FA and ATM in carcinogenesis and mediating sensitivity to chemotherapy agents? Using the ATM/FA/BRCA molecular crossroads as a starting point, this session will focus on clinical, epidemiological, functional and therapeutic aspects to provide a detailed overview and attempt to answer these questions.

 

8:00 AM   The molecular crossroads of ataxia telangiectasia, Fanconi anemia and hereditary breast/ovarian cancer. M. Tischkowitz. Univ. of Cambridge.

8:30 AM   Characterizing cancer risks in carriers with mutations in the FA/BRCA and ATM genes. A. C. Antoniou. Univ. of Cambridge.

9:00 AM   Ataxia-telangiectasia: From phenotype to biology, and onto treatment strategies. Y. Shiloh. Sackler Sch. of Med., Tel Aviv.

9:30 AM   Targeting the FA/BRCA pathway in cancer therapy. A. D. D'Andrea. Dana-Farber Cancer Inst.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 5 – Does the Increasingly Blurry Distinction between Research and Clinical Care Create an Obligation to Actively Search for Secondary Findings in Genomic Research or Otherwise Change the Relationship Between Researchers and Participants?

Room TBD, Convention Center

Moderators: Benjamin E. Berkman, NHGRI/NIH
  Stacy Gray, Dana Farber Cancer Inst.

The rise of next-gen sequencing has raised questions about how best to negotiate the management of large quantities of uncertain human DNA sequence information in ways that reconcile the demands and expectations of researchers, clinicians, regulators and patients/participants. Particularly acute is the debate about what responsibilities, if any, researchers have to disclose secondary findings. Assuming there is some obligation to disclose certain incidental findings that are inadvertently discovered in the course of research, is there a positive obligation to search for these findings? And if so does this obligation extend beyond identifying risks for “actionable” severe or life-threatening diseases? The standard view has been that researchers are not obligated to fulfill a clinical role of actively searching for incidental findings, but this assumption seems to be relatively unexamined. An argument for a duty to look finds support in the fact that genomic researchers are often in a unique position to help their participants through application of the knowledge, abilities and resources they hold as scientists and/or physicians. On the other hand, with finite resources and legal constraints, there is often a tension between the research agenda and provision of ancillary care to participants. The “duty to look” question is arguably synecdochic: given the potential of whole-genome/whole-exome sequencing to uncover clinically relevant variants, is the research-clinical distinction still viable in a human genomic context? And should the heterogeneous wishes of research participants and patients be taken into consideration? This session will explore both the narrow issue of whether there is a duty to look for secondary genomic findings as well as the broader questions of how large-scale sequencing results should be governed, the a priori obligations researchers have (and don't have) to participants, and the epistemology of research versus medicine in a genomic age that is both blurrier and more transparent.

 

8:00 AM   Why researchers do not have a duty to look for incidental findings. E. W. Clayton. Vanderbilt Law Sch.

8:30 AM   Appropriately - but narrowly - defining a researcher's obligations to look for incidental findings. J. P. Evans. Univ. of North Carolina at Chapel Hill.

9:00 AM   Neither duty nor prohibition: Using private ordering to transcend 'one-size-fits-all' in large-scale sequencing of human beings. M. N. Meyer. Harvard Law Sch.

9:30 AM   What we've got here is failure to communicate: the growing disconnect between 20th-century research protections and individual agency in an age of whole-genome sequencing. M. Angrist. Duke Inst. for Genome Sciences & Policy.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 6 – Evidence-Based Genetic Counseling for Clinical Genome Sequencing

Room TBD, Convention Center

Moderators: Shelin Adam, Univ. of British Columbia
  Myra Roche, Univ. of North Carolina at Chapel Hill

The current standard of care in providing clinical genetic counseling continues to rely on face-to-face encounters, occurring at specific times and places, usually prior to, and/or following, genetic testing. Yet there is little empirical evidence to demonstrate that this model is an optimal one for enhancing informed decision-making and communicating genetic test results; two critical goals of genetic counseling. Attempts to study the effectiveness of this traditional model have often focused on recall of quantitative information such as recurrence risk, which is disappointingly poor. However, aside from knowledge, other factors have also been suggested as important outcomes. Furthermore, serious doubts have been raised about the appropriateness of the current model and its ability to be scaled up to the volume, complexity and potential implications of clinical sequencing. Alternative models such as e-learning platforms are now beginning to be used for both education and counseling. Such computer-based systems can be designed to present flexibility in literacy level, prior knowledge of genomics and interest level, have the advantage of accessibility at locations, times and circumstances that are most convenient for the family, and provide information that is consistent with current science. However, are we sacrificing effectiveness for practicality and cost? This session will summarize the current counseling model as well as alternative, multi-media options for providing genetic counseling for genome sequencing. We will discuss the need for more evidence, and provide examples of validated methods that can be used to gather robust outcome data regarding the effectiveness of genetic counseling.

 

8:00 AM   Evidence-based genomic counseling for 21st century medicine. M. J. Khoury. Ctrs. for Dis. Control and Prevent.

8:30 AM   Measuring patient benefits from genetic counseling and testing interventions: Is patient empowerment a useful outcome? M. McAllister. Cardiff Univ.

9:00 AM   Can an e-learning platform provide adequate genetic counseling? P. Birch. Univ. of British Columbia.

9:30 AM   Online genetic education and counseling — lessons from a direct-access genotyping service. U. Francke. 23andMe Inc., Mountain View, CA.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 7 – Functional Interpretation of Genomes Using Biological Networks

Room TBD, Convention Center

Moderator: Kasper Lage, Massachusetts Gen. Hosp.

The recent explosion in genome-wide association studies, exome sequencing projects, and epigenetic data sets, have revealed many genetic variants likely to be involved in disease processes, but the composition and function of the molecular systems they affect remain largely obscure. This limits our progress towards biological understanding and therapeutic intervention. Computational analyses that systematically integrate biological networks (i.e., networks in which genes are connected if they are functionally associated in some experimental system) with genetic data have emerged as a powerful approach to functionally interpret large genomic data sets by enabling the identification of de novo pathways perturbed in disease. This session will highlight algorithms, statistics, and web portals being developed in this area, and exemplify how different network-based methods have been used to analyze common and rare genetic variants, as well as epigenetic data sets. We will introduce specific methods being developed and applied by leaders in the field, which will enable the audience to use these tools in their work. Furthermore, we will exemplify how draft molecular systems involved in immunological, metabolic, muscular, cardiovascular, and psychiatric disorders have been elucidated by coupling genetic data and biological networks through rigorous statistical frameworks.

 

8:00 AM   Integrating biological networks and genetics to reverse engineer molecular systems driving diseases. K. Lage. Massachusetts Gen. Hosp.

8:30 AM   Cell-type specificity of gene networks to understand disease biology. S. Raychaudhuri. Brigham and Women's Hosp.

9:00 AM   Using networks, functional genomics resources and signals of selection to understand hundreds of complex disease loci. J. Barrett. Wellcome Trust Sanger Inst., Hinxton, U.K.

9:30 AM   Network-based association models for exome-sequencing data. S. Purcell. Mount Sinai Sch. of Med.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 8 – Insights from Large Scale Sequencing

Room TBD, Convention Center

Moderators: Goncalo R. Abecasis, Univ. of Michigan Sch. of Publ. Hlth.
  Gabor Marth, Boston Col.

Large-scale genomic sequencing studies are fueling rapid advances in many areas of human genetics. Many of the opportunities (such as our ability to conveniently access rare and even private variants in many individuals) and challenges (such as the large volumes of data that must be managed) are shared across many areas of application. It is also clear that different fields have elected to focus on quite different strategies for data generation, ranging from deep whole genome sequencing, to deep targeted sequencing of exomes or even smaller regions, to shallow whole genome sequencing. Approaches to data analysis also vary, including both analysis based on mapping (where interpretation is guided by the reference genome) and emerging assembly-based analytical approaches (where interpretation might eventually become independent of the reference). In this session, we will compare and contrast advances in studies of Mendelian disorders, cancer sequencing, complex trait analysis, genome informatics and population genetics and discuss how they are deploying sequencing-based approaches, examples of success for each area, and challenges and opportunities for the future. The goal of this set of presentations is to show how different people can look at the same interesting, new data and come up with very different (and valuable) interpretations.

 

8:00 AM   Mechanistic and clinical advances from sequencing cancer patients. N. Rahman. Inst. of Cancer Res., Sutton, U.K.

8:30 AM   Accelerating Mendelian genetics. D. Nickerson. Univ. of Washington Sch. of Med.

9:00 AM   Whole genome mapping, assembly and analysis. H. Li. Broad Inst. of Harvard and MIT.

9:30 AM   Population genetic insights from 10,000s of human samples. J. Novembre. Univ. of Chicago.


Wednesday, October 23

8:00 AM–10:00 AM

Concurrent Invited Session I (3-9)

SESSION 9 – Population Based Animal Models for Discovery of Complex Traits

Room TBD, Convention Center

Moderators: John French, NIEHS/NIH, Research Triangle Park
  Kimberly McAllister, NIEHS/NIH, Research Triangle Park

Understanding human gene by environment interactions is difficult due to uncontrolled individual differences in host susceptibility to individual variation in multiple stressors (chemicals, infections, etc.) over a lifetime. Appropriate experimental models can be used to identify morbidity and disease for epidemiology research or confirm observations from epidemiology under controlled conditions with multiple variables. Over the past decade, members of the complex traits community have led the development of new and powerful mouse resources for quantitative genetics. These new mouse populations are designed to model human genetic diversity with approximately 45 million segregating SNPs, CNV, and structural variants. The Collaborative Cross (CC) is a population of advanced intercross recombinant inbred lines (AIRILs) created from a randomized eight-way intercross of inbred strains and subsequently inbred to fix each genetically diverse genome. Selected generations of breeders from the CC AIRILs were then used to create the diversity outbred (DO) mice. The CC AIRILs and the DO mice are critical tools for mapping and validating candidate genes identified from QTLs using molecular biology and reverse genetics approaches. New research results will be presented in this session that demonstrate a discovery approach that can facilitate identification of genetic or epigenetic variants associated with factors that interact to determine phenotypic outcome to environmental and genetic variations at the population level. Experimental and quantitative genetic approaches will likely enable the identification of genetic variants that contribute to differential responses in humans to environmental exposures and thus corroborate genetic epidemiology and provide new targets for human investigation.

 

8:00 AM   High-resolution genetic mapping using the mouse collaborative cross and diversity outbred populations. G. Churchill. The Jackson Lab.

8:30 AM   Genomic characterization of house dust mite-induced allergic airway disease in mice. S. Kelada. Univ. of North Carolina at Chapel Hill.

9:00 AM   Host genetics and modulation of the gut microbiome as a means to understanding metabolic function. A. Benson. Univ. of Nebraska-Lincoln.

9:30 AM   Mapping susceptibility QTLs for gene-environment interactions and environmental toxicity. J. French. NIEHS/NIH, Research Triangle Park.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 37 – Community Efforts to Decipher the Phenotypic Impact of Genomic Variation

Room TBD, Convention Center

Moderators: David H. Ledbetter, Geisinger Hlth. Syst., Danville, PA
  Joyce A. Mitchell, Univ. of Utah

Significant decreases in the cost of sequencing have led to the generation of large amounts of genomic data from patients, both in the research and clinical settings. However, as more and more variants are identified in individuals with and without disease, interpreting these variants has become a bottleneck, particularly given that a massive percentage of genetic variation is rare or weak in its effect. It has become clear that the only path forward is to enable a broad community effort in data sharing. This session will address the critical components of data sharing needed to support a community effort in deciphering the phenotypic impact of genomic variation. Speakers will cover the development of standards for documenting phenotypes and classifying variants with respect to pathogenicity. Speakers will also provide an update on NCBI's public resources, including the ClinVar database, as a mechanism for data sharing. Progress on populating the database with useful data and optimizing it for use in advancing genomic medicine will be discussed.

 

4:30 PM   Developing approaches to support the community in the evaluation, deposition and curation of genomic variants. C. L. Martin. Geisinger Hlth. Syst., Danville, PA.

5:00 PM   Assessing the evidence for causality of sequence variants: Establishing community standards. D. MacArthur. Massachusetts Gen. Hosp.

5:30 PM   Developing standards to represent human phenotypes. A. Hamosh. Johns Hopkins Univ. Sch. of Med.

6:00 PM   Using ClinVar as a resource to evaluate genomic variation: A clinical laboratory's perspective. S. J. Bale. GeneDx Inc., Gaithersburg, MD.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 38 – Genetics of Non-communicable Diseases in sub-Saharan Africa

Room TBD, Convention Center

Moderators: Eleftheria Zeggini, Wellcome Trust Sanger Inst., Hinxton, U.K.
  Adebowale Adeyemo, NHGRI/NIH

Genome-wide association studies (GWAS) have revolutionized the field of complex trait genetics but the vast majority of GWAS conducted to date have been carried out in populations of European descent. There is a widely-recognized paucity of well-powered genetic association studies in African populations, mainly driven by global inequalities in resources. Sustainable research infrastructure and enhanced collaborative networks for genomic studies supported by research funding bodies (e.g. through the H3Africa Initiative) are transforming the landscape. Pronounced genetic diversity across ethnic groups in sub-Saharan Africa (SSA), in conjunction with low levels of linkage disequilibrium (LD) and differences in haplotype structure, give rise to challenges when conducting large-scale genomic epidemiology studies in SSA populations. Emerging SSA GWAS can lead to novel discoveries and additionally inform strategies for designing powerful trans-ethnic meta-analysis and fine-mapping studies.

 

4:30 PM   The African Genome Variation Project. F. Tekola-Ayele. NHGRI/NIH.

5:00 PM   Developing genomic research in Africa: The case for sickle cell disease. J. Makani. Muhimbili Univ. of Hlth. and Allied Sci., Tanzania.

5:30 PM   Discovering podoconiosis susceptibility genes: From molecules to disease control for a neglected tropical disease. M. Newport. Brighton and Sussex Med. Sch.

6:00 PM   Genomic studies of cardiometabolic traits in sub-Saharan Africa. M. Sandhu. Wellcome Trust Sanger Inst., Hinxton, U.K.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 39 – Guilty by Annotation: The Role of Non-coding Variation in Phenotypic Variation and Disease

Room TBD, Convention Center

Moderators: Stephen B. Montgomery, Stanford Univ.
  Emmanouil T. Dermitzakis, Univ. of Geneva

Functional genomic sequencing has highlighted extensive non-coding genome function. New transcribed sequences and protein-DNA binding regions have being increasingly identified en masse. To understand the impact of diverse genetic variation and somatic mutation, even those unique to single individuals, current and future studies will leverage information from these increasingly high-throughput functional genomics assays. Such information, when integrated together into models that predict trait predisposition will likely improve our ability to understand diverse etiologies of rare and complex disease. This session will discuss how genetic variation influences noncoding genome function through (1) expression genetic studies and (2) epigenetic studies and highlight how such information can be used to identify noncoding variants influencing or underlying (3) cancer, (4) loss of function variation and complex disease.

 

4:30 PM   Finding causal regulatory variants with genome and transcriptome sequencing. E. T. Dermitzakis. Univ. of Geneva.

5:00 PM   Regulatory genomics and epigenomics of complex disease genetics for fine-mapping and genome-wide integration. M. Kellis. MIT.

5:30 PM   Functional analysis of polymorphisms identified using genome-wide association studies. J. Taipale. Univ. of Helsinki.

6:00 PM   Interpreting loss-of-function variation and complex disease association using RNA-Seq and ChIP-Seq data. S. B. Montgomery. Stanford Univ.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 40 – Human Genetics of Common Infectious Diseases

Room TBD, Convention Center

Moderators: Laurent Abel, INSERM/Univ. Paris Descartes
  Erwin Schurr, McGill Univ.

Epidemiological and experimental evidence is accumulating to indicate that human genetics plays a major role in the development of infectious diseases after exposure to most microbes. Many studies have shown that rare life-threatening infectious diseases in children can result from Mendelian predispositions leading to selective susceptibility to a given microbe. However, the genetic determinism of most common infectious diseases, especially in adults, remains unclear and involves more complex genetic predisposition. Limited success has been achieved so far in the genetic dissection of common infectious diseases using genome-wide approaches such as GWAS or positional cloning strategies.) Alternative strategies are needed and will be discussed and illustrated in four major infectious diseases (HIV infection, malaria, tuberculosis and leprosy) such as: 1) decreasing genetic heterogeneity by focusing on subgroups of patients defined on the basis of individual/clinical factors (e.g. age and specific phenotypes in leprosy) or extrinsic factors (e.g. pathogen variability in tuberculosis); 2) searching for rare variants through high-throughput sequencing (in HIV infection); 3) using new approaches to define candidate regulatory regions (in tuberculosis and malaria); and 4) using HLA expression data as a quantitative trait to provide functional validation of initial association findings (HIV infection). The human genetic dissection of infectious diseases is of major importance to develop new approaches for prevention and treatment based on pathophysiology (e.g. boosting or restoring a specific immune response) at a time when the emergence and spread of new and drug-resistant infectious agents pose vital threats to humankind.

 

4:30 PM   Immunogenetic variation characterizing exceptional control of HIV. M. Carrington. Frederick Natl. Lab., Frederick, MD.

5:00 PM   Human genetics and the risk of infectious diseases. D. B. Goldstein. Duke Univ. Sch. of Med.

5:30 PM   Human genetics of leprosy: novel insights. E. Schurr. McGill Univ.

6:00 PM   Human genetic studies on tuberculosis and malaria. R. Horstmann. Bernhard Nocht Inst. for Trop. Med., Hamburg.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 41 – Informed Consent for Whole Genome Sequencing: Experience and Implications for Practice

Room TBD, Convention Center

Moderators: Stephanie M. Fullerton, Univ. of Washington Sch. of Med.
  Holly K. Tabor, Seattle Children's Hosp.

Whole genome sequencing (WGS), and related next-gen approaches to genetic investigation, have emerged as predominant research strategies with tremendous analytical and clinical promise. While the number of individuals whose genomes have been sequenced is expanding rapidly, best practice with respect to informed consent for such sequencing is not yet settled. Not only are the benefits and risks of involvement imperfectly understood, the near-certain prospect of generating clinically relevant findings must be communicated, and where possible, participant preferences with respect to the offer of particular types of findings solicited. Clearly conveying such complexities in a time-limited invitation to participate in research, and/or testing in a clinical setting, is challenging and important questions remain with regard to the types of information conveyed, the modes of communication employed, the expertise required of the individuals doing the consenting, the range of choices presented, and the ability to revisit consent preferences as the study unfolds. These and related challenges will be discussed, and empirical data on the efficacy and acceptability of specific approaches in a range of studies from the NHGRI and NCI supported Return of Result and Clinical Sequencing Exploratory Research Programs, will be presented.

 

4:30 PM   Research goals and informed consent in clinical genomics research. J. C. Sapp. NHGRI/NIH.

5:00 PM   Informed consent and its role in eliciting result return preferences. W. K. Chung. Columbia Univ.

5:30 PM   Consent, assent, and WGS studies of children. I. A. Holm. Boston Children's Hosp.

6:00 PM   Informed consent for large-scale clinical mutation testing: anticipating the future. R. R. Sharp. Cleveland Clin.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 42 – Multimodal Treatment of Lysosomal Storage Diseases as a Portal to Emergent Genetic Therapies

Room TBD, Convention Center

Moderator: Ari Zimran, Shaare Zedek Med. Ctr., Jerusalem

The Orphan Drug Act, enacted 30 years ago, enabled sufferers of rare disorders to benefit from commitment of pharmaceutical companies to prioritize development of orphan drugs for circumscribed patient populations. Among the first options was intravenous Enzyme Replacement Therapy (ERT) for visceral signs and symptoms of Gaucher disease which has proven to be safe and effective (placental Ceredase® and recombinant Cerezyme®, Genzyme Corporation; Cambridge MA) as have the company's impressive international compassionate programs. Biosimilar ERT with VPRIV® (Shire HGT, Cambridge MA) and Elelyso® (Protalix Therapeutics, Carmiel Israel) were introduced prior to (FDA) regulatory approval (February 2010 and May 2012, respectively) because of a global shortage in Cerezyme supply. Nonetheless, despite their putative increased safety (e.g., lower antibody rates and non-mammalian system, respectively) and possible improved efficacy, these are also expensive and intravenous. Other modalities, particularly substrate reduction therapy (SRT) and pharmacological chaperones (PC) administered orally, may provide added safety, convenience, quality of life, and may prove to be considerably less costly. We will provide updated profiles on these different treatment modalities in the context of therapeutic models for other single gene disorders. Nevertheless, the availability of a specific therapy, especially for the patients who present at an early age, has altered the composite patient profiles of patients, for instance since the devastating and life-threatening sequelae are less likely to occur as early as they once did. Thus, the current concerns in the post-specific therapy era are radically different than heretofore and will be presented in the context of various LSDs.

 

4:30 PM   Enzyme replacement therapy. G. A. Grabowski. Cincinnati Children's Hosp.

5:00 PM   Substrate reduction therapy. G. Pastores. NYU Sch. of Med.

5:30 PM   Pharmacologic chaperones. O. Goker-Alpan. Ctr. for Clin. Trials, O&O Alpan, Fairfax, VA.

6:00 PM   Future perspectives. D. Elstein. Shaare Zedek Med. Ctr., Jerusalem.


Thursday, October 24

4:30 PM–6:30 PM

Concurrent Invited Session II (37-43)

SESSION 43 – Nonhuman Primate Genomics: Evolutionary Insights and Relevance to Human Phenotypes

Room TBD, Convention Center

Moderators: Jeffrey M. Kidd, Univ. of Michigan
  Tomas Marques-Bonet, CSIC-Univ. Pompeu Fabra, Barcelona

In the last 20 years, there have been tremendous advances in our understanding of the genetic diversity of the human species. However, a systematic effort to obtain comparable datasets for other primates species (great apes, Old World monkeys and New World monkeys) has been somewhat forgotten. Human variation can only be interpreted if we have a complete understanding of the biological processes that shape it. In the last years, greatly aided by advances in sequencing capacities, research in primate genomics has expanded such that the field of primate population genomics has emerged. The benefits of such efforts are multifaceted and include a variety of disciplines in biology including human evolution and the use of primates as model organisms to study human diseases. This symposium brings together expert talks from the broad categories of genome evolution, population genetics, and complex trait genetics to describe recent advances in primate population genomics and to relate the continued relevance of non-human primates for understanding human genetic diversity.

 

4:30 PM   Great ape versus human genetic diversity: The Great Ape Genome Project. T. Marques-Bonet. CSIC-Univ. Pompeu Fabra, Barcelona.

5:00 PM   Where ancestry runs deep: Ancient balancing selection in humans. M. Przeworski. Univ. of Chicago.

5:30 PM   Genomic insights into chromosomal evolution in Gibbons. L. Carbone. Oregon Hlth. & Sci. Univ.

6:00 PM   Mapping complex traits in non-human primates. N. Freimer. UCLA.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 70 – Design, Content and EMR Integration of Clinical Sequencing Reports

Room TBD, Convention Center

Moderators: Robert C. Green, Brigham and Women's Hosp./Harvard Med. Sch.
  Heidi L. Rehm, Partners Ctr. for Personalized Genet. Med., Cambridge, MA

This session will present data and describe recent developments in the design, content and implementation of clinical reports for exome and genome sequencing. Presenters will initially discuss how such a report may be designed, how much information it should present on primary and secondary findings and how accessible it should be to clinicians who are not genetic specialists. Data will be presented on how well clinicians understand and can effectively use such reports in clinical practice. As clinical sequencing becomes more common, the integration of such reports to the electronic medical record (EMR) will be critical. Data will be presented on how ongoing clinical genomics research programs are attempting to integrate findings with the EMR and on the usability of specific solutions to scaling such integration and providing decision support.

 

9:30 AM   Design and implementation of the General Genome Report. R. C. Green. Brigham and Women's Hosp./Harvard Med. Sch.

10:00 AM   Reporting results not directly related to the indication for testing. C. Eng. Baylor Col. of Med.

10:30 AM   Approaches to integrating next-generation sequencing into the electronic health record. P. Tarczy-Hornoch. Univ. of Washington.

11:00 AM   Scaling genomic reporting and clinical decision support. H. L. Rehm. Partners Ctr. for Personalized Genet. Med., Cambridge, MA.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 71 – More or Less: Copy Number Variation and Human Adaptation

Room TBD, Convention Center

Moderators: Chack-Yung Yu, The Ohio State Univ.
  Ed J. Hollox, Univ. of Leicester

Inter-individual copy number variation (CNV) of genomic DNA sequences is an important mechanism that drives the diversity of phenotypes and contributes to differential disease susceptibilities. The role of gene loss and gene gain in evolution has been discussed for many years. However, only recently have studies shown that continuous gain or loss of DNA sequences have played an important role in the speciation of humans and other primates, and of adaptation within a species to different environments. Phenotypes involved include human-specific brain morphology, the lack of a penile spline in men, and variation in resistance to infectious disease between populations. Genetic mechanisms include duplication and divergence of coding DNA sequences, and deletion of regulatory DNA sequences. Scientific approaches range from detailed structural and functional characterization of single loci to genomewide overviews across multiple species. In this session, we will present an overview of the latest research, demonstrating the long strides that have been made in linking the evolution of phenotype to molecular changes in the genome.

 

9:30 AM   Evolution of segmental duplications and novel neural genes. E. E. Eichler. Howard Hughes Med. Inst. and Univ. of Washington.

10:00 AM   Human-specific loss of regulatory DNA and the evolution of human-specific traits. D. M. Kingsley. Howard Hughes Inst. and Stanford Univ. Sch. of Med.

10:30 AM   Primate structural genomic variation evolving under positive selection. C. Lee. Brigham and Women's Hosp.

11:00 AM   Structural variation of beta-defensins: Welcome to the dynamic genome. E. J. Hollox. Univ. of Leicester, U.K.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 72 – Somatic Mutations in Human Disease — Piecing Together the Mosaic

Room TBD, Convention Center

Moderators: Leslie Biesecker, NHGRI/NIH
  William Dobyns, Univ. of Washington

Our field is dominated by three genetic disease concepts' ‘simple’ Mendelian disorders, complex disorders, and the complex somatic genetics of cancer. Recently, a new model is coming to the fore, that of the simple mosaic disorder – disorders caused by mosaicism for a mutation in a single gene. This model is on the rise because recent genomic techniques have improved detection of genomic alterations in mosaic tissues. These developments are accelerating the discovery of a wide array of human disease that is attributable to mosaic mutations. While it has long been known that gonadal mosaicism can explain recurrence of dominant disorders and that cancer is a complex mosaic genomic disease, only now are we beginning to appreciate the breadth and frequency of mosaic disorders. While the mosaic disorders of dermatologic disorders and overgrowth are most readily recognizable, mosaicism can affect any tissue and may explain a substantial fraction of human disease. The session will begin with the phenotypes of mosaic disorders, emphasizing dermatologic disorders to set the clinical context for the session. Second will be a review of the molecular genetics of mosaic cytogenetic and copy number variation, as elucidated initially by microscopic and now SNP array analysis. Third will be an overview of the disorders caused by mosaic point mutations in genes and we will close with a presentation on how lessons from cancer relate to simple mosaicism. These presentations will provide the participants with a broad overview and understanding of the role of somatic variation in human disease.

 

9:30 AM   The clinical manifestations of mosaicism. R. Happle. Freiburg Univ. Med. Ctr., Germany.

10:00 AM   Cytogenetics and the historical context of mosaicism. N. Spinner. Univ. of Pennsylvania.

10:30 AM   Single gene mutations and mosaic genetic disease. L. Biesecker. NHGRI/NIH.

11:00 AM   The mosaic landscape of cancer. E. Mardis. Washington Univ. Sch. of Med.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 73 – Tandem Repeat-Associated Epigenetic Mechanisms in Neuromuscular Disorders

Room TBD, Convention Center

Moderators: Paul J. Hagerman, Univ. of California, Davis, Sch. of Med.
  Laura Ranum, Col. of Med., Univ. of Florida

This session will consider four classes of repeat-expansion disorders, each with a distinct epigenetic mechanism, all of which are linked through repeat-length regulation of pathogenesis. The remarkable range of mechanisms include decreased epigenetic repression through macrosatellite contraction; toxic RNA gain-of-function and epigenetic silencing as outcomes of CGG-repeat expansion, with the switch in mechanisms depending only on the length of the CGG repeat; shifts to non-canonical translation initiation and the production of potentially toxic peptide products (CAG-repeat disorders); and epigenetic gene silencing associated with long-intronic GAA-repeat expansions. The session will highlight the newly acquired knowledge from basic research in the area of repeat-associated disorders, will describe new research tools and methodologies that have made the research advances possible, and will relate how such knowledge can be used to guide the diagnosis and treatment of these and other repeat-associated disorders.

 

9:30 AM   Facioscapulohumeral dystrophy: An epigenetic disease with genetic modifiers. S. Tapscott. Fred Hutchinson Cancer Res. Ctr., Seattle.

10:00 AM   Mechanisms of pathogenesis in fragile X-associated disorders. P. J. Hagerman. Univ. of California, Davis, Sch. of Med.

10:30 AM   Repeat associated non-ATG translation in microsatellite expansion disorders: Lessons from SCA8 and myotonic dystrophy. L. Ranum. Col. of Med., Univ. of Florida.

11:00 AM   Development of histone deacetylase inhibitors as therapeutics for Friedreich's ataxia. J. Gottesfeld. The Scripps Res. Inst.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 74 – Twin Studies: Helping Us Understand and Exploit the Genome (In Honor of Walter Nance's Contributions to Human Genetics on his 80th Birthday)

Room TBD, Convention Center

Moderators: Rita M. Cantor Chiu, David Geffen Sch. of Med. at UCLA
  Cynthia C. Morton, Brigham and Women's Hosp.

This session will focus on current realized and proposed successes in genetic epidemiology and genomics using twins. The history of twin studies will be summarized, and current applications to genetic epidemiology which illuminate the question of ‘missing heritability’ and refocus investigations will be presented. The use of twin registries and large population samples will be contrasted. Methods that reveal pathways for complex disorders will be discussed. Applications that have successfully developed baseline information regarding DNA, genes, structural variants, epigenetics and gene expression will be presented. The overarching rationale will be to celebrate Walter Nance's creative contributions to twin studies and to encourage ASHG researchers and clinicians to see their value and apply them. Information regarding availability of twin resources and how to interpret the results of twin research will be included.

 

9:30 AM   Twin studies in the non-molecular era. W. Nance. Virginia Commonwealth Univ.

10:00 AM   Twin studies as a tool in genetic epidemiology. N. Risch. UCSF.

10:30 AM   Twin studies as a powerful approach to identifying and understanding molecular pathways that underlie complex traits. N. Martin. Queensland Inst. of Med. Res., Brisbane.

11:00 AM   Twin studies as a valuable approach to omics research. T. Spector. Kings Col. London.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 75 – Where Do Risk Variants Act? Interrogating Genomic Studies of Multiple Human Tissues

Room TBD, Convention Center

Moderators: Chris Cotsapas, Yale Sch. of Med.
  Kristin Ardlie, Broad Inst. of MIT and Harvard

We now know thousands of genetic variants that influence a range of human traits and disease outcomes. As most of these variants are non-coding, the challenge is to understand what gene regulatory processes they perturb – and in which cell types. To do so requires comprehensive regulatory profiles across human tissues. Several large-scale projects are currently addressing this need, using genomic technologies such as RNA sequencing and epigenetic profiling to describe detailed regulatory profiles across large cohorts of donors. The task now is to uncover which genetic variants affect gene regulation in each tissue, and how this results in organism-level phenotypic changes. This session will bring together leaders of projects including GTEx, the ENCODE, the Roadmap Epigenome Project and ImmVar, who will describe their ongoing efforts to create meaningful regulatory profiles across tissues, how these may be used to mechanistically interpret GWAS and medical resequencing results and identify relevant cell-types for disease.

 

9:30 AM   Leveraging gene expression data to understand cell autonomous effects of inflammatory disease variants. P. De Jager. Brigham and Women's Hosp.

10:00 AM   Cross-tissue meta-analytic approaches result in large gains in regulatory variant identification. B. Raby. Brigham and Women's Hosp.

10:30 AM   Unique opportunities for scientific discovery in transcriptome studies across multiple tissues. N. Cox. Univ. of Chicago.

11:00 AM   Regulatory effect mapping of trait-associated variation identifies causal cell types. J. Stamatoyannopoulos. Univ. of Washington.


Saturday, October 26

9:30 AM–11:30 AM

Concurrent Invited Session III (70-76)

SESSION 76 – Whole Genome Sequencing for Every Baby? Where Diagnostic and Screening Applications Collide.

Room TBD, Convention Center

Moderators: James O'Leary, Genet. Alliance, Washington, DC
  Natasha Bonhomme, Genet. Alliance, Washington, DC

With the transition from research to clinical applications of whole genome/exome sequencing (WG/ES) well under way, it is critical that we focus on the future public health applications of these technologies. What decisions (knowingly or unknowingly) are being made now regarding the development of these technologies that will affect their viability for use in public health screening? What would it mean for these technologies to enter mainstream use and become integrated into state newborn screening (NBS) programs? This session will not only explore the potential of WGS in the newborn period, but also its appropriateness. What research has been completed or needs to be completed to properly address the ethical, legal and social issues surrounding this application? And finally, what are the practical hopes and concerns that researchers, clinicians, public health practitioners, consumers, and policy-makers have about a potential future where every baby receives WGS at birth?

 

9:30 AM   Genomic technology and newborn screening — pros and cons. O. A. Bodamer. Univ. of Miami Miller Sch. of Med.

10:00 AM   WGS in newborn screening: What are we screening for? J. R. Botkin. Univ. of Utah.

10:30 AM   Parental interest in whole genome sequencing of newborns. A. Goldenberg. Case Western Reserve Univ.

11:00 AM   Does the public want to have every baby sequenced at birth? Public participation and expectations of WGS. Y. Bombard. Univ. of Toronto, Li Ka Shing Knowledge Inst., Toronto.


Saturday, October 26

11:45 AM–1:15 PM

SESSION 77 – ASHG Distinguished Speakers Invited Symposium: Medical Systems Genomics

Hall B2, Level 0 (Lower Level), Convention Center

Moderators: Jeff Murray, Univ. of Iowa
  Andrew G. Clark, Cornell Univ.

This symposium will provide the ASHG community with an update from a trio of trailblazing experts on the state of the art of Systems Biology and its applications to medical genetics. Aviv Regev, Marc Vidal, and Trey Ideker will provide varying perspectives on the use of omics data to build predictive models of physiological states of the cell and the organism, including diseased states. These integrative approaches can provide a particularly informative picture of changes in cellular function mediated by cancer, pathogen response, and other stresses. They will challenge us with what the prospects are for methods like these to deliver improved insights regarding disease risk and therapeutic interventions. The speakers will conclude by gazing into the future, providing a vision of where systems medicine will be going in the next decade.

 

   Interactome networks and human disease. M. Vidal. Dana-Farber Cancer Inst., Harvard Univ.

   Understanding cancer genomes with networks. T. Ideker. UCSD.

   Reconstructing cellular circuits: From individual to single cell variation in immune cells. A. Regev. Broad/MIT/HHMI.

 

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