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Invited Listing

 

Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 3 – Implementing of Next-Generation Sequencing as a Clinical Test

Hall D, Lower Level North, Moscone Center

Moderators: Nazneen Aziz, Col. of American Pathologists, Lexington, MA
  Ira Lubin, Ctr. for Dis. Control and Prevent.

Next-generation sequencing (NGS) is used widely in clinical research for the discovery of disease-associated genes and the clinical community is beginning to embrace this technology for diagnostic testing. The rapid evolution of NGS technologies presents significant opportunities and challenges for researchers and clinicians for improving health outcomes; particularly with respect to an increased emphasis on personalized and preventive medicine. Adoption of NGS in the clinical laboratory setting requires the adoption of many processes and procedures, such as, the analytic and clinical validation of the test, CLIA/CAP certification, standards for reference materials for proficiency testing, and questions regarding reimbursement and informed consent. This session will initially review the state of NGS in the clinical setting today and what is anticipated in the near future. This will be followed by consideration for what is practically needed for clinical adoption of NGS such as regulatory and professional standards, development, availability, and access to reference materials, and the laboratory professional’s role for ensuring high quality test results that are useful for informing clinical decision making. This session will be informative and practical for the researcher and laboratorians who are considering launching NGS as a clinical test.

 

8:00 AM   Challenges of introducing NGS in the clinical laboratory. S. Richards. Oregon Hlth. & Sci. Univ.

8:15 AM   Addressing the fundamentals: NGS validation and implementation in a clinical setting. M. Hegde. Emory Univ.

8:45 AM   Proficiency testing, quality control and development of reference material for NGS clinical testing. E. Lyon. Univ. of Utah Sch. of Med.

9:00 AM   Development of accreditation standards for laboratories offering NGS as a clinical test. N. Aziz. Col. of American Pathologists, Lexington, MA.

9:30 AM   Lessons from the clinic—What’s next? H. Jacob. Med. Col. of Wisconsin.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 4 – Assessing the Pathogenicity of Genetic Variants: Translating in Vitro and in Silico Advances to the Clinic

Gateway Ballroom 103, Lower Level South, Moscone Center

Moderators: Marc S. Greenblatt, Univ. of Vermont
  Sean V. Tavtigian, Univ. of Utah

Interpreting which genetic variants are pathogenic and which are not remains a critical challenge in the genetics of hereditary cancer syndromes and other inherited disorders. Genetic testing for disorders such as Lynch syndrome (caused by mutations in DNA mismatch repair genes) and hereditary breast-ovarian cancer (BRCA1, BRCA2 genes) often identifies a ‘Variant of Uncertain Significance’ (VUS). As DNA sequencing capacity increases at a furious pace, there is an ever greater need to have effective methods to analyze these data. There is a consensus in the field of genetic testing that proper classification of variants requires the integration of multiple types of data. Some lines of evidence are familiar to clinicians (e.g., segregation of an allele with disease, detailed phenotype), and others are less familiar (e.g., in vitro protein functional assays, in silico algorithms based on gene sequence or protein structure). Ideally, integration can be done in a quantitative way, such as Bayesian probabilistic analysis, but qualitative data may be used if quantitative measurements are not possible. This session will 1) explore recent advances in applying and integrating statistical, laboratory, and computational methods in the classification of missense, splice site, and other genetic variants, and 2) report on international collaborations that are using these methods to classify variants in mismatch repair, BRCA, and other genes and disseminating validated conclusions to the cancer genetics community.

 

8:00 AM   Innovative in vitro and in vivo assays to investigate the function of mismatch repair gene variants in Lynch syndrome. N. de Wind. Leiden Univ. Med. Ctr., Netherlands.

8:30 AM   Analysis of splicing abnormalities to define pathogenic variants in cancer susceptibility genes. A. B. Spurdle. Queensland Inst. of Med. Res., Australia.

9:00 AM   Integrating in silico with in vitro, statistical, and phenotype data to classify missense variants: A paradigm that is ready for translation to the clinic. S. V. Tavtigian. Univ. of Utah.

9:20 AM   CAGI: The Critical Assessment of Genome Interpretation, a community experiment to evaluate phenotype prediction. S. E. Brenner. Univ. of California, Berkeley.

9:40 AM   International collaborations to establish standards for classifying genetic variants and to disseminate results. M. S. Greenblatt. Univ. of Vermont.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 5 – Gene Regulatory Change: The Engine of Human Evolution?

Room 135, Lower Level North, Moscone Center

Moderators: James P. Noonan, Yale Univ. Sch. of Med.
  Nadav Ahituv, UCSF

What makes us human? Classic human traits, such as language and sophisticated tool use, are the result of physical changes during human evolution, including increased brain complexity and altered limb morphology. This session will focus on efforts to identify evolutionary changes in gene regulation that produced uniquely human phenotypes. Speakers will describe novel approaches that are empowering research in this emerging field, and the insights that are being gained. Topics to be discussed include: 1) Computational identification of putative gene regulatory elements that changed extensively during human evolution; 2) The role of repetitive elements in generating novel regulatory functions; 3) Human-specific loss of developmental regulatory elements; 4) New methods to link phenotypic and genotypic variation across closely related species, and the implications for understanding human-specific biology and disease; and 5) Identifying human-specific developmental regulatory changes by direct comparisons of enhancer function and gene expression in embryonic human and nonhuman primate tissues using functional genomics. The session will illustrate how the synthesis of diverse computational and experimental approaches is beginning to reveal the genetic basis of unique human biology.

 

8:00 AM   Chromatin profiling of human embryonic tissues identifies regulatory elements with human-specific developmental functions. J. P. Noonan. Yale Univ. Sch. of Med.

8:25 AM   Many human accelerated regions are developmental enhancers. K. S. Pollard. UCSF.

8:50 AM   Linking human and mammalian genotypes to phenotype. G. Bejerano. Stanford Univ.

9:15 AM   The role of repetitive elements in driving human and mammalian genome regulation. D. Odom. Cancer Research UK, Cambridge, U.K.

9:40 AM   Evidence of regulatory turnover in the human lineage revealed by comparing mammalian constraint, human diversity, and biochemical activity. M. Kellis. MIT.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 6 – Insights into Human Demography and Selection from Full Genome Sequencing

Room 134, Lower Level North, Moscone Center

Moderators: Jeffrey M. Kidd, Univ. of Michigan
  Carlos D. Bustamante, Stanford Univ.

Next-generation sequencing allows geneticists to directly test the extent and pattern of natural selection in the human genome. These new genomic data address previous concerns of ascertainment bias and accurate identification of causal alleles. Recently, population geneticists have proposed multiple, strong positive sweeps related to diet and immune defense, pervasive negative selection in and nearby genes, and adaptation by allele frequency shifts from standing variation. The proportion of the human genome attributable to these different patterns is currently under intense debate. Furthermore, selection is operating on the background of complex human demography, such as long-range continental migrations and population-specific bottlenecks. This symposium aims to provide diverse viewpoints on the different modes of selection operating on the human genome and a discussion of how demographic processes may have constrained evolution in both recent and ancient human history.

 

8:00 AM   The effect of out-of-Africa migrations on the distribution of deleterious alleles in diverse human genomes. B. M. Henn. Stanford Univ.

8:30 AM   Genetic adaptations to new environments in humans. A. Di Rienzo. Univ. of Chicago.

9:00 AM   Insights into selective sweeps and diversity from thousands of sequenced genomes. R. Hernandez. UCSF.

9:30 AM   A genomic view of the demographic and adaptive history of African pygmies. L. Quintana-Murci. Inst. Pasteur, Paris, France.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 7 – Age-Related Macular Degeneration—GWAS and Beyond: Guiding Light for the Complex Neurodegenerative Diseases

Gateway Ballroom 104, Lower Level South, Moscone Center

Moderators: Anand Swaroop, NEI/NIH
  Hemin Chin, NEI/NIH

AMD is a complex multi-factorial neurodegenerative disease that is a major cause of visual impairment in the elderly. Genetic linkage and genome-wide association studies (GWAS) have been immensely successful in identifying genetic susceptibility load in AMD and in providing insights into cellular pathways underlying pathogenesis of the disease . Numerous groups worldwide have validated the strong association of variants at CFH and ARMS2/HTRA1 loci with AMD risk, and genome-wide association studies have suggested the involvement of complement, extracellular matrix, angiogenesis and HDL cholesterol pathways. This session will discuss the current progress to carry out comprehensive genetic analyses of AMD, highlighting experimental approaches that may be applicable to other complex traits and multigenic diseases. The speakers in this session will provide the current status of meta-analysis of AMD-GWAS, targeted resequencing, and whole exome sequencing efforts to discover or search for rare causal variants and functional pathways, and diagnostic/therapeutic implications of genetic variants. Additionally, we will discuss the relevance of AMD genetics for other complex neurodegenerative diseases and the future of genetic studies.

 

8:00 AM   The bigger the better: Searching for novel loci for age-related macular degeneration in a large consortium effort. I. Heid. Regensburg Univ. Med. Ctr., Germany.

8:30 AM   From genetic association to causal alleles by resequencing and exome arrays: The stage after GWAS. G. Abecasis. Univ. of Michigan.

9:00 AM   An integrated hypothesis of the development and progression of age-related macular degeneration based upon available genetic and biological data. G. S. Hageman. Univ. of Utah.

9:30 AM   An updated recipe for Mendel’s pea soup. M. A. Pericak-Vance. Univ. of Miami Miller Sch. of Med.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 8 – "Yes Virginia, Family Studies Really Are Useful for Complex Traits in the Next-Generation Sequencing Era" (session in honor of Dr. Robert Elston's contributions to human genetics in the year of his 80th birthday)

Room 124, Lower Level North, Moscone Center

Moderators: Michael A. Province, Washington Univ. in St. Louis
  Francoise Clerget-Darpoux, INSERM U781, Univ. Paris V, France.

The pros and cons of family designs as NGS targets in dissecting complex traits are presented. In the linkage era, family studies were ubiquitous, but they were largely neglected in the GWAS era, which concentrated mostly on unrelated subjects. But as attention now moves from the common to the rare variants that can only be completely interrogated through sequencing, it is useful to at least consider whether the designs that were optimal for GWAS remain so for NGS studies. Pedigrees seem to have at least some advantages over studies of unrelateds for studying rare variation. First, it may be easier to distinguish true rare variant calls from sequence errors in family designs than it is in unrelated cohorts, since there is the added dimension of pedigree consistency information, especially for low coverage. Second, a key statistical challenge to analyzing the phenotype/genotype correlation with rare variants, is finding enough copies of any one variant allele with which to make inferences (hence the various collapsing or burden tests, which combine multiple nearby rare variants into a single test). For any given very rare allele, sampling additional unrelateds is an inefficient strategy to find more copies of that allele, whereas family members of allele carriers are much more likely to be allele carriers themselves. On the other hand, a disadvantage of family designs is that there is a smaller diversity of founder mutations, so less of the overall population of alleles is measured per individual. This session emphasizes the results of real sequencing studies in pedigrees as well as simulation results to delineate the areas in which family designs offer advantages and where they offer disadvantages over sequencing unrelated subjects, such as case-control designs.

 

8:00 AM   Whole genome sequencing in large pedigrees for the identification of human QTLs. J. Blangero. Texas Biomed. Res. Inst., Austin.

8:30 AM   Linkage and association information should be considered as complementary and not redundant. F. Clerget-Darpoux. INSERM U781, Univ. Paris V, France.

9:00 AM   Power to find rare causal variants in pedigrees. M. A. Province. Washington Univ. in St. Louis.

9:30 AM   Whither human genetics? R. C. Elston. Case Western Reserve Univ.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 9 – Surveying Customer Responses to Personal Genetic Services

Room 132, Lower Level North, Moscone Center

Moderator: J. Scott Roberts, Univ. of Michigan

This session will feature presentation of empirical data on the responses of personal genome testing consumers to their individual genomic information. Dr. David Kaufman of Johns Hopkins University will discuss publicly available interpretations of individual whole genome sequence data in light of his Center's prior work on direct-to-consumer (DTC) testing and return of individual genetic research results. Dr. Cinnamon Bloss of the Scripps Genomic Health Initiative (SGHI) will present new long-term follow-up data from the SGHI, including data related to DTC pharmacogenomic testing and genetic ancestry testing. Dr. Sandra Lee of Stanford University will describe an anthropological study of how the public integrates information on population genetic variation in their interpretation of individualized genetic risk information for disease and drug response. The session will conclude with a panel discussion moderated by Dr. Scott Roberts of the University of Michigan, joint PI (with Dr. Robert Green at Brigham and Women’s Hospital) of the Impact of Personal Genomics (PGen) Study. The PGen Study is a longitudinal survey study examining consumers’ response to personal genome testing, including their motivations and expectations, risk perceptions, health behaviors and intentions. Two personal genomics companies, 23andMe and Pathway Genomics, are collaborators on the PGen Study, and the closing panel will feature a discussion that includes company representatives Dr. Joanna Mountain and Dr. Tanya Moreno. In this discussion, panelists and audience members will share their perspectives on the potential benefits and risks involved in research partnerships between academicians and personal genomics companies.

 

8:00 AM   Interpretomics: Using studies of DTC testing and the return of research results to shape the interpretation of personal whole genomic sequence data. D. Kaufman. Genet. and Publ. Policy Ctr., Johns Hopkins Univ.

8:30 AM   Impact of DTC genomic testing at long-term follow-up. C. S. Bloss. Scripps Translational Sci. Inst. and Scripps Hlth.

9:00 AM   Rendering population differences meaningful: A study of consumer interpretation of genetic diversity. S. S-J. Lee. Stanford Univ. Med. Sch.

9:30 AM   The role of personal genomic testing companies in research: A panel discussion featuring industry and academic perspectives. J. Mountain1, T. Moreno2, J. S. Roberts3. 1) 23andMe Inc., Mountain View, CA; 2) Genomics Corp., San Diego; 3) Univ. of Michigan.


Wednesday, November 7

8:00 AM–10:00 AM

Concurrent Invited Sessions I (3-10)

SESSION 10 – Metabolism, Metals, and Neurodegeneration: Toward Enhanced Understanding of Disease Mechanisms and Rational Therapeutics

Room 130, Lower Level North, Moscone Center

Moderators: Stephen G. Kaler, NICHD/NIH
  Susan J. Hayflick, Oregon Hlth. & Sci. Univ.

This session will focus on the expanding knowledge concerning the influence of inborn errors of metabolism and disorders of trace metal homeostasis on neurodegeneration. Increasing numbers of clinical phenotypes and molecular defects are now associated with disordered metabolism in the central and peripheral nervous systems. These include Alzheimer and Parkinson diseases, Menkes and Wilson diseases, ATP7A-related distal motor neuropathy, acetyl CoA transporter 1-related hypocupremia, pantothenate kinase-associated neurodegeneration, infantile neuroaxonal dystrophy, dystonia-parkinsonism, Friedreich ataxia, hemochromatosis, and iron sulfur cluster scaffold myopathy. Expert speakers will discuss and review translational research advances relevant to these conditions, as well as emerging data on disease mechanisms, pathophysiology, and potential novel remedies.

 

8:00 AM   Alzheimer disease and the metal hypothesis. R. E. Tanzi. Massachusetts Gen. Hosp.

8:30 AM   Neurodegeneration with brain iron accumulation. S. J. Hayflick. Oregon Hlth. & Sci. Univ.

9:00 AM   Friedreich ataxia and diseases of iron sulfur cluster assembly. T. A. Rouault. NICHD/NIH.

9:20 AM   Neurodegeneration and disorders of copper transport. S. G. Kaler. NICHD/NIH.

9:40 AM   Exploring the link between glucocerebrosidase mutations and Parkinson disease. E. Sidransky. NHGRI/NIH.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 21 – Mendelian Randomization: Using Genetic Variants to Inform Causality in Observational Epidemiology

Room 135, Lower Level North, Moscone Center

Moderators: David M. Evans, Univ. of Bristol, U.K.
  Lyle J. Palmer, Univ. of Ontario, Canada

A central problem in classical observational epidemiology concerns whether an association between a medically relevant exposure and a disease outcome reflects a causal relationship, or whether the purported association is a spurious result of latent confounding, bias or reverse causality. For example, does an inverse correlation between red wine drinking and heart disease, mean that red wine prevents heart attacks? The gold standard in proving whether an association reflects a causal relationship is the randomized controlled trial (RCT), in which participants are randomly assigned into groups that differ on average only in terms of their treatment (exposure) effect. However, RCTs are typically expensive, of long duration and in some cases, ethically or practically infeasible to implement. Mendelian randomization is a relatively new methodology that uses genetic variants that have been robustly associated with medically relevant exposures from genetic association studies (e.g. genetic variants related to BMI, smoking, alcohol etc.) to determine whether these exposures are truly causally related to disease outcomes. This session describes the principles behind Mendelian randomization, explains how Mendelian randomization can be used in epidemiological and gene expression studies to assess causality, describes its assumptions and limitations, and finally discusses extensions and promising alternatives to the method.

 

8:00 AM   Mendelian randomization: Overcoming the limitations. G. D. Smith. Univ. of Bristol, U.K.

8:30 AM   Utilizing multiple variants to improve Mendelian randomization studies. B. Pierce. Univ. of Chicago.

9:00 AM   Application of Mendelian randomization analyses in prospective studies from Denmark. A. Tybjærg-Hansen. Univ. of Copenhagen, Denmark.

9:30 AM   Mendelian randomization for HDL levels and implications for clinical risk prediction. B. F. Voight. Univ. of Pennsylvania Sch. of Med.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 22 – Common and Rare CNVs: Genesis, Patterns of Variations and Human Diseases

Hall D, Lower Level North, Moscone Center

Moderators: Chack Yung Yu, Nationwide Children's Hosp. and The Ohio State Univ.
  Edward J. Hollox, Univ. of Leicester, U.K.

Copy number variation (CNV) is a part of human genomic variation. There are two types of CNVs. The first type is common CNVs that occur at regions with complex genomic structures and engage genes involving in gene-environment interactions. The diversity of common CNVs both in terms of copy number and sequence variation is remarkable, yet because of their complex and challenging nature, they are under-studied. The second type is de novo or recent CNVs involving deletions and duplications of genomic DNA fragments that are rare individually but moderately frequent collectively, particularly among subjects with developmental, neurologic and psychiatric disorders. This session will highlight the complexity of common CNVs and discuss their roles in immune-mediated and cognitive diseases. In addition, the session will feature mechanistic studies to understand the generation of CNVs, and illustrate techniques for the detection and quantification of common and rare CNVs.

 

8:00 AM   CNVs engaged in immune complex handling and autoimmune diseases: Complement C4 and immunoglobulin Fc-gamma receptors. C. Y. Yu. Nationwide Children’s Hosp. and The Ohio State Univ.

8:30 AM   Human lineage-specific CNVs: DUF1220 domain copy number linked to cognitive disease and brain evolution. J. M. Sikela. Univ. of Colorado Sch. of Med., Aurora.

8:55 AM   TAR: A mixed genomic disorder caused by a low-frequency regulatory SNP combined with a 1q21.1 microdeletion. W. H. Ouwehand. Cambridge Univ. and Wellcome Trust Sanger Inst., Cambridge, U.K.

9:20 AM   Genetic and environmental risk factors for de novo CNVs. T. W. Glover. Univ. of Michigan.

9:40 AM   Frequency estimation of low-level somatic mosaicism for pathogenic CNVs. P. T. Stankiewicz. Baylor Col. of Med.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 23 – Advancing Gene Therapy to the Clinic: Molecular Medicines Come of Age

Gateway Ballroom 104, Lower Level South, Moscone Center

Moderator: Beverly Davidson, Univ. of Iowa

The first evidence for uptake and expression of exogenous DNA in mammalian cells occurred in the 60s and 70s, and in 1980 the first experiment was performed in which patients were given plasmid DNA expressing protein lacking in their blood cells. Over the next 25 years researchers focused on improved vector development and better delivery modalities, along with more appropriate clinical trial design, to improve the chances to positively impact disease course in patients with genetic diseases. In this symposium we will present exciting advances in gene therapy for the eye (Jean Bennett), the liver (Kathy High), blood disorders (Maria-Gracia Roncolo), the leukodystrophies (Nathalie Cartier), and lysosomal storage diseases affecting the brain (Beverly Davidson). Data presented will span from preclinical studies in animal models to advanced clinical trials in affected individuals using several vector platforms.

 

8:00 AM   Safety and efficacy of AAV-mediated gene transfer to liver for severe hemophilia B. K. High. Children’s Hosp. of Philadelphia.

8:25 AM   Safety and efficacy after AAV2 re-administration in subjects with congenital blindness due to RPE65 mutations. J. Bennett. Univ. of Pennsylvania.

8:45 AM   Advancing gene therapy for ADA-SCID and beyond. M-G. Roncarolo. Univ. Vita-Salute San Raffaele., Milan, Italy.

9:10 AM   Gene therapy for the leukodystrophies. N. Cartier. Saint Vincent de Paul Hosp., Paris, France.

9:30 AM   AAV gene therapy for childhood onset neurological disease caused by lysosomal enzyme deficiencies. B. Davidson. Univ. of Iowa.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 24 – RNA Splicing in Human Development, Diseases and Natural Variation

Room 124, Lower Level North, Moscone Center

Moderators: David E. Symer, The Ohio State Univ. Comprehen. Cancer Ctr.
  Richard A. Padgett, Lerner Res. Inst., Cleveland

RNA splicing has been identified and studied for decades, but its roles in normal human biology and in contributing to human diseases have not been fully described to date. The presentations in this session will address the latest breakthroughs in understanding how RNA splicing and processing contribute to human development, diseases including various cancers and neurodegeneration, and natural variation. Also discussed will be the development of animal models of aberrant RNA splicing, and optimization of the latest technologies of RNA-seq and bioinformatics analysis of RNA splicing variation.

 

8:00 AM   Functional consequences of minor spliceosomal snRNA mutations in human development and natural variation. D. E. Symer. The Ohio State Univ. Comprehen. Cancer Ctr.

8:25 AM   Multicopy snRNA genes and neurodegeneration. S. L. Ackerman. HHMI/The Jackson Lab., Bar Harbor, ME.

8:50 AM   Understanding the chemical mechanisms and biological implications of splicing reactions. R. A. Padgett. Lerner Res. Inst., Cleveland.

9:15 AM   Overlaying RNA maps onto human disease. R. B. Darnell. HHMI and Rockefeller Univ.

9:40 AM   Biological insights from RNA-seq: Learning the rules of RNA splicing specificity. C. Burge. MIT.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 25 – Genomic Medicine: ELSI Goes Mainstream

Room 132, Lower Level North, Moscone Center

Moderators: Wylie Burke, Univ. of Washington
  James P. Evans, Univ. of North Carolina at Chapel Hill

Next-generation sequencing of the human genome has the potential to predict disease risk, identify disease causation, and refine therapeutic interventions. As research-based sequencing moves into clinical practice, however, a number of ethical and social questions will enter mainstream practice, and will need to be addressed in a practical manner to inform best practices. For example, how do key stakeholders (patients, providers, researchers, and the public) view the risks and benefits of genome sequencing, and how can benefits be optimized and risks mitigated? How do we address children’s rights as well as other family members’ rights with respect to potentially shared information learned from sequencing individuals? Empirical data can contribute to a better understanding of these issues; but what kinds of data are most relevant and how can they be used to inform practice and policy? How do we navigate the increasingly blurred line between research and clinical care? These issues will be discussed and empirical data presented by a panel of experts investigating the ethical and social issues of genome sequencing in a variety of research and patient populations.

 

8:00 AM   Views of patients, parents of patients, and clinicians toward whole genome sequencing for clinical care management. A. A. Lemke. Med. Col. of Wisconsin.

8:30 AM   My46: An innovative web-based approach to managing and returning results from exome and whole genome sequencing. H. K. Tabor. Seattle Children’s Hosp.

9:00 AM   Returning "actionable" results to family members in a pancreatic cancer biobank: Views of probands and family members. B. Koenig. Sch. of Nursing, UCSF.

9:20 AM   Approaches and attitudes on return of WGS/WES results. K. Ormond. Stanford Univ.

9:40 AM   Next steps in development of best practices for use of genome sequencing in clinical care. . A. McGuire. Baylor Col. of Med.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 26 – Model Organism Genetics, Human Biology and Human Disease

Gateway Ballroom 103, Lower Level South, Moscone Center

Moderators: Phil Hieter, Univ. of British Columbia
  Hal Dietz, Johns Hopkins Univ. Sch. of Med.

Yeast, worms, flies, zebrafish, and mice are key ‘model’ organisms that offer powerful experimental approaches for the study of biological processes relevant to human biology and disease. The genome sequencing projects of the 1990s reemphasized the striking extent to which all organisms are built from the same genes, and highlighted the enormous value of model experimental organisms for the study of evolutionarily conserved gene function. Few, if any, processes at the gene level are known to be unique to humans. Indeed, key aspects of most human disorders can be modeled in experimentally tractable organisms through the analysis of orthologous genes and pathways, using the genetic, biochemical and cell biological toolboxes that have been developed in each model organism. This symposium will accent the current relevance of model organism studies for the understanding, diagnosis, and treatment of human disease, and anticipate the future role of model organisms in human disease research. We chose to highlight a diverse set of biological processes and experimental systems to make the point that the principles of cross species analysis of basic gene function extend to the study of all human disorders.

 

8:00 AM   Budding yeast: Lessons from yeast applied to the study of human genetic diseases of protein traffic. R. Schekman. Univ. of California, Berkeley.

8:30 AM   The nematode worm: Mechanisms regulating aging in worms and man. C. Kenyon. UCSF.

9:00 AM   The zebrafish: Zebrafish heart development and function. D. Stainier. Max Planck Inst. for Heart and Lung Res., Bad Nauheim, Germany.

9:30 AM   The laboratory mouse: Mouse models of glaucoma and retinal ganglion cell loss. S. John. HHMI/The Jackson Lab., Bar Harbor, ME.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 27 – Next-Generation Sequencing in Isolated Populations: Opportunities for Accelerated Gene Discovery in Complex Traits

Room 134, Lower Level North, Moscone Center

Moderators: William K. Scott, Univ. of Miami
  Jeffrey R. O'Connell, Univ. of Maryland Baltimore

This session will present recent developments in the application of whole-exome or whole-genome sequencing (collectively ‘next-generation sequencing’ or NGS) in samples from genetically isolated populations. Such populations have long been the focus of gene discovery efforts for complex traits because of the hypothesized reduction in the genetic complexity of the trait, and the enrichment of rare alleles. Prior genome-wide linkage efforts could detect large genomic regions potentially harboring rare alleles, while genome-wide association efforts could detect smaller areas with more common alleles. NGS allows the direct examination of both common and rare alleles and can be analyzed in both frameworks. Characterisics of isolated population may facilitate the blending of NGS with these prior approaches, by deep sequencing a small number of individuals to use as a reference panel for imputation within pedigrees or on the population level, by ‘filtering’ detected variants against pedigree relationships (or kinship estimates) in individuals with the trait. However, since the structure of the population must be taken into account, application of existing reference panels or methods for these analyses must be done carefully. The speakers for this session will discuss approaches to using NGS data for gene discovery for complex traits in isolated populations, reviewing methodologic approaches specific to such studies and illustrating their use in data sets drawn from such populations.

 

8:00 AM   Using low-pass whole genome sequencing to create a reference population for genome imputation in an isolated population: Examples from the SardiNIA study. S. Sanna. Cittadella Univ. di Monserrato, Italy.

8:30 AM   Fine-mapping linkage of age-related traits using whole-exome sequencing in a midwestern Amish population sample. W. K. Scott. Univ. of Miami.

9:00 AM   The many-of-few: The power of genetic isolates for discovery and function of rare variants. J. R. O'Connell. Univ. of Maryland Baltimore.

9:30 AM   Studying rare variants in the Genetic Research in Isolated Populations program. C. van Duijn. Erasmus Med. Ctr. Rotterdam, Netherlands.


Thursday, November 8

8:00 AM–10:00 AM

Concurrent Invited Sessions II (21-28)

SESSION 28 – Transforming Medical Student Education in Genetics and Genomics: How Do We Improve Health and Individualize Care through Medical School Genetic and Genomic Curricula?

Room 130, Lower Level North, Moscone Center

Moderators: Joann N. Bodurtha, Johns Hopkins Univ.
  Joan Scott, NCHPEG, Lutherville, MD

This session will provide national perspectives on integrating genetics and genomics in medical student education. Controversies, ranging from the marketing of curriculum change to addressing personal genotyping, and lessons learned will be emphasized. Challenges in 4-year integration, evaluation, ethical issues and competing priorities will be included. Drs. Valle, Burke, and Potocki will describe 3 different models of curriculum development and delivery. Drs. Demmer and Salari will provide contrasting experiences in introducing personal genotyping by students into the curriculum.

 

8:00 AM   Genes to Society—3 years of implementation. D. Valle. Johns Hopkins Univ.

8:30 AM   The Vermont Integrated Curriculum: The UVM experience. L. Burke. Univ. of Vermont Col. of Med.

8:55 AM   Effecting change: Building a genetics curriculum that supports the physicians of tomorrow. L. Potocki. Baylor Col. of Med.

9:20 AM   Lessons learned from the introduction of personalized genotyping into a medical school curriculum. L. Demmer. Carolinas Medical Center.

9:40 AM   Personal genotyping in a medical school curriculum on genomics and personalized medicine. K. Salari. Stanford Univ. Sch. of Med.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 73 – Returning Results from Large-Scale Sequencing: Where the Rubber Meets the Road

Gateway Ballroom 103, Lower Level South, Moscone Center

Moderators: Leslie G. Biesecker, NHGRI/NIH
  Robert C. Green, Brigham and Women’s Hosp.

Medicine is on the brink of a revolution, as large-scale medical sequencing (LSMS) is now available for patient care, marking the dawn of genomic medicine. LSMS may be used in patients with a family history or symptoms of a disease for diagnosis or to predict future health risks for prevention and surveillance. Developing standards and procedures for the use of LSMS in clinical medicine is critical and there is a need for empiric data to determine how to interpret, analyze, and return results. A critical question is how to handle secondary findings from LSMS. Speakers in this session will share their pioneering research initiatives that explore the translation of LSMS into meaningful clinical information and the delivery to patients. The speakers will report on a range of studies, including patients ascertained with diseases, healthy volunteers, adults, and children, research versus clinical, and rare versus common disease. All of the speakers will focus on results, and not just opinions, to inform the practice of genomic medicine and future research studies on the return of results. Dr. Biesecker will introduce the session and present ClinSeq, a large cohort LSMS study with return of results to subjects. Dr. Green will present the results of two efforts to formulate consensus on return of incidental findings in LSMS. Dr. Kingsmore will present experience with neonatal and pediatric diagnosis by LSMS. Finally, Dr. Veltman will present the results of a pilot using LSMS to diagnose genetically heterogeneous diseases with required return of all medically relevant results.

 

9:40 AM   ClinSeq: A pilot study of large-scale medical sequencing in research and implications for clinical genomic medicine. L. G. Biesecker. NHGRI/NIH.

10:10 AM   Expert concordance and discordance for return of incidental findings from whole genome sequencing. R. C. Green. Brigham and Women’s Hosp.

10:40 AM   Using next-generation sequencing for carrier testing for severe childhood recessive diseases. S. F. Kingsmore. Children’s Mercy Hosp., Kansas City, KS.

11:10 AM   Diagnostic implementation of exome sequencing: Results from 500 patients. J. Veltman. Genomic Disorders Nijmegen, Netherlands.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 74 – Genomic Approaches to Mendelian Disorders

Hall D, Lower Level North, Moscone Center

Moderators: Jay Shendure, Univ. of Washington
  David Valle, Johns Hopkins Univ. Sch. of Med.

Although the gene(s) underlying approximately 3,000 Mendelian disorders are known, there are thousands of well-defined or suspected Mendelian disorders for which the genetic basis remains unknown. The past three years have been witness to an explosion of interest in applying new technologies such as exome and genome sequencing to identify the genetic basis of Mendelian disorders that have proven intractable to conventional strategies. In this session, we will describe the progress as well as current challenges facing efforts to scale and accelerate the application of next-generation technologies to Mendelian disorders, e.g. the U.S.-based Mendelian Genome Centers as well as related international efforts. Topics that will be explored include primary research results from leading groups in this field; advances and ongoing challenges in phenotype curation, sequencing technology, and data analysis; and the broader implications of these efforts for biology and medicine.

 

9:40 AM   Genomic approaches to Mendelian disorders. D. Valle. Johns Hopkins Univ. Sch. of Med.

9:55 AM   FORGE Canada: A nation-wide effort to understand the genomics of childhood disorders. K. Boycott. Children’s Hosp. of Eastern Ontario, Canada.

10:10 AM   Current challenges in exome or genome-based analysis of Mendelian disorders. J. Shendure. Univ. of Washington.

10:40 AM   Lessons from 500 diagnostic exomes. H. G. Brunner. Radboud Univ. Nijmegen Med. Ctr., Netherlands.

11:10 AM   Genes, genomes and the future of medicine. R. Lifton. Yale Univ.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 75 – Emerging Applications of Identity by Descent Segment Detection

Gateway Ballroom 104, Lower Level South, Moscone Center

Moderators: Sharon R. Browning, Univ. of Washington
  Brian L. Browning, Univ. of Washington

Identity by descent (IBD) is fundamental to genetics and has diverse applications. Recently developed statistical methods and genome-wide SNP data have made it possible to detect haplotypes shared identically by descent between individuals with common ancestry up to 25-50 generations ago. With sequence data, shared haplotypes from even more distant ancestry can be detected. Patterns of IBD segment sharing within and between populations reveal important population demographic features including recent effective population size and migration patterns. IBD segment sharing is directly relevant to disease gene mapping and estimation of heritability. Individuals who share a genetic basis for a trait are more likely have IBD sharing compared to randomly chosen individuals, and this forms the basis for IBD mapping and heritability estimation. Analysis of data from extended pedigrees was extremely difficult with standard linkage approaches, but is now possible using approaches based on detected IBD segments. Detected IBD can be present across pedigrees, which enhances power to detect association with the trait. Further, in population samples there is potential to utilize detected IBD segments to improve power to detect association when multiple variants within a gene influence the trait. IBD segments can also be used to greatly improve haplotype phase estimates, which is critical to understanding the functional consequence of genetic variation. IBD-based long-range phasing has previously been shown to be effective in isolated populations such as Iceland, but recent advances have extended its application to large outbred populations. In this session, we explore these exciting new developments.

 

9:40 AM   Sharing by descent, phasing, rare variants and population structure. A. Kong. deCODE Genet., Reykjavik, Iceland.

10:10 AM   Length distributions of identity by descent reveal fine-scale demographic history. I. Pe'er. Columbia Univ.

10:40 AM   Identity by descent within and between pedigrees. E. A. Thompson. Univ. of Washington.

11:00 AM   Using high resolution identity by descent: From detecting selection to explaining trait variability. M. Abney. Univ. of Chicago.

11:20 AM   Extending the limits of IBD segment detection with sequence data and new statistical methods. B. L. Browning. Univ. of Washington.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 76 – The Functional Consequences of microRNA Dysregulation in Human Disease

Room 134, Lower Level North, Moscone Center

Moderators: Cheryl L. Thompson, Case Western Reserve Univ.
  Ahmad Khalil, Case Western Reserve Univ.

MicroRNAs (miRNAs) are an evolutionarily conserved class of small non-coding RNAs that have been shown to regulate the expression levels of numerous protein-coding genes. Although integral to animal biology, their role in human disease has only recently been studied. Previously, numerous miRNAs have been demonstrated to be dysregulated in multiple diseases, including cancer, cardiovascular disease, neurological disease and many others. However, the exact functions and mechanisms of these miRNAs in human diseases are yet to be fully elucidated. A number of recent studies have now begun to shed light on the role of miRNAs in disease, providing insights into mechanisms for imitation and progression of disease as well as targets for preventive and therapeutic intervention. In this session we have assembled a group of world leaders in the field of miRNA and human diseases. The speakers will discuss their latest research on miRNAs, which will cover a range of topics from targets of miRNAs, animal models of miRNA action as well as the role of circulating miRNAs in diagnostics.

 

9:40 AM   Causes and consequences of microRNA dysregulation in cancer. C. Croce. The Ohio State Univ.

10:10 AM   OncomiR-1 in cancer and development: A tale of mice and men. A. Ventura. Sloan-Kettering Inst.

10:40 AM   microRNA reprogramming in cancer: Mechanisms and consequences. J. Mendell. Univ. of Texas Southwestern Med. Ctr.

11:00 AM   Exploring circulating miRNAs as blood-based diagnostic biomarkers. M. Shapero. Affymetrix, Santa Clara, CA.

11:20 AM   Circulating microRNAs in obesity and postmenopausal breast cancer. C. L. Thompson. Case Western Reserve Univ.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 77 – Centralizing the Deposition and Curation of Human Mutations

Room 132, Lower Level North, Moscone Center

Moderators: Robert L. Nussbaum, UCSF
  David H. Ledbetter, Geisinger Hlth. Syst., Danville, PA

Hundreds of thousands of disease-causing variants have been identified in patients with disease, yet only a small fraction of that data, and the interpretation of it, is accessible to researchers and clinicians. The centralization of data on human genomic variation is a critical step in accelerating advances within the field of genomic medicine. Such centralization of variant data will not only enable more efficient approaches to data analysis, but will also ensure the use of a uniform set of standards across the many communities contributing data and intending to use the resources for research and clinical applications. This session will highlight groups that have recently joined efforts to solve this challenge and create a free and useful human genomic mutation database for the community.

 

9:40 AM   Improving the accuracy of variant identification. D. Church. NLM/NIH.

10:10 AM   The ISCA Consortium: Standardization and sharing of structural variation data. C. L. Martin. Emory Univ. Sch. of Med.

10:40 AM   Introducing ClinVar. D. Maglott. NCBI, NLM/NIH.

11:10 AM   Community involvement in centralized mutation curation. H. L. Rehm. Harvard Med. Sch.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 78 – Stem Cells and Personalized Medicine

Room 135, Lower Level North, Moscone Center

Moderator: Stephen H. Tsang, Columbia Univ.

Speakers will discuss applications of patient-specific and disease-specific stem cell lines, including disease modeling, drug screening, and regenerative medicine. Panelists will bring experience in clinical genetics, genetic manipulation in stem cells, and disease modeling. The FDA has recently approved phase I/II clinical trials to investigate the safety and efficacy of embryonic stem cell-based retinal cell transplantation, but such therapy requires immunosuppression. Patient-specific stem cells may offer an alternative to embryonic stem cells that will skirt the need for immunosuppressive therapy as well as the social and political ramifications of embryonic stem cell research, but their utility even extends far beyond such groundbreaking advances.

 

9:40 AM   Stem cells and personalized medicine in retinal degenerations. S. H. Tsang. Columbia Univ.

10:10 AM   Direct reprogramming to generate patient-specific stem cells and neurons. M. Wernig. Stanford Sch. of Med.

10:40 AM   A chemical approach to controlling cell fate. S. Ding. UCSF.

11:10 AM   Patient-specific stem cells and cardiovascular genetics. B. Conklin. UCSF.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 79 – Should Noninvasive Prenatal Diagnosis Augment or Replace Current Prenatal Screening and Diagnosis?

Room 124, Lower Level North, Moscone Center

Moderators: Mark E. Nunes, Kaiser Permanente, San Diego
  Mildred K. Cho, Stanford Univ.

The discovery of circulating cell-free fetal nucleic acid (cffDNA) in maternal blood plasma in 1997 allowed for the development of noninvasive prenatal diagnosis (NIPD) offered commercially in a medical setting in North America beginning in October 2011. From the initial discovery, ethical issues were raised in that the method could most easily be validated seeking circulating Y chromosome transcripts. The method subsequently has been validated for fetal Rh typing and fetal aneuploidy, but the next-generation sequencing methods used to analyze cffDNA allow any Mendelian trait or disorder with a known gene to be detected by the method. This technology convergence, coupled with the test being offered at 10-weeks gestation, could provide a level of access and choice in women’s reproductive decision making unprecedented since the introduction of oral contraception. We will briefly introduce the topic, and then debate the ethical, legal, and social issues of broadening the scope and availability of NIPD. The technique will be placed in the context of the history of seeking fetal markers and cells in maternal circulation. The ethical context will be outlined, with competing issues of autonomy and societal interest. The legal context, within the current debate surrounding reproductive freedom, will be discussed. The possible impact on society and medical practice will be described.

 

9:40 AM   Lessons from the clinical introduction of noninvasive prenatal diagnosis: How we got here. A. T. Bombard. Sequenom Inc., San Diego.

10:05 AM   Cell-free fetal DNA in prenatal diagnosis: Where we are going? D. Bianchi. Tufts Univ., Boston.

10:30 AM   Academia and industry in the development of noninvasive prenatal diagnosis. M. K. Cho. Stanford Univ.

10:55 AM   Ethical and policy implications of early noninvasive prenatal diagnosis. J. S. King. UC Hastings Col. of the Law, San Francisco.

11:20 AM   Discussion. M. E. Nunes. Kaiser Permanente, San Diego.


Saturday, November 10

9:40 AM–11:40 AM

Concurrent Invited Sessions III (73-80)

SESSION 80 – Selection Signatures and the Genetics of Autoimmunity and Infectious Diseases

Room 130, Lower Level North, Moscone Center

Moderators: Judy H. Cho, Yale Univ.
  Richard A. Spritz, Univ. of Colorado Denver Anschutz Med. Campus

The overlap of autoimmune and infectious disease loci is one of the seminal findings of the GWAS era. The presence of a relatively limited and recurring number of major autoimmune and infectious disease-associated genes and pathways may well correspond with functional networks that evolved in response to historically significant infectious pathogens. It may be speculated that the plethora of common functional polymorphisms identified through GWAS in autoimmune diseases evolved through positive selection; in subsequent eras and environmental conditions, these once beneficial polymorphisms confer increased susceptibility to autoimmunity. Support for this concept is provided by the observation that uncommon, often highly penetrant, mutations in overlapping genes and pathways are associated in infectious diseases such as severe mycobacterial infections. Predictive functional networks may be optimized by integration of complementary data sources, notably selection signatures. Novel approaches of identifying signatures of positive selection at single and multiple loci will require integration of genetic association data with biologic data that optimally models relevant selection conditions.

 

9:40 AM   The genetics of autoimmunity. J. H. Cho. Yale Univ.

9.55 AM   The genetics of autoimmunity. R. A. Spritz. Univ. of Colorado Denver.

10:10 AM   Selection signatures and mechanisms of host-microbe interactions. P. Sabeti. Harvard Univ.

10:40 AM   Interactions of HLA class I with killer-cell immunoglobulin-like receptors: Influences on human disease. P. Parham. Stanford Univ.

11:10 AM   Toward a genetic theory of infectious diseases. J.-L. Casanova. Rockefeller Univ.


Saturday, November 10

12:00 NOON–1:00 PM

SESSION 81 – Closing Plenary: Human Genetics 2012 and Beyond: Present Progress and Future Frontiers

Hall D, Lower Level North, Moscone Center

Moderator: Joel N. Hirschhorn, 2012 Program Committee Chair
Boston Children's Hosp., Harvard Med. Sch. and Broad Inst.

Presenter: Chris Gunter, HudsonAlpha Inst. for Biotechnol.

Panelists:
Han Brunner, Radboud Univ. Nijmegen
Jay Shendure, Univ. of Washington
Dian Donnai, Univ. of Manchester
Lynn Jorde, Univ. of Utah
Hal Dietz, Johns Hopkins Univ.

An outstanding panel of expert human geneticists with varying perspectives will make will make brief presentations and then participate in a wide-ranging discussion on the most exciting advances and important upcoming challenges in their areas of human genetics.Topics will be driven by questions from the panelists and the audience, but will include many of the following perspectives:

  • The importance of education for the public, scientists, and clinicians

  • The impact of new technology on human genetics and genomics

  • Advances that define biological mechanisms

  • Challenges of interpretation of exome and genome sequencing

  • Translation of advances into clinical care

During the course of the 62nd Annual Meeting, registrants are encouraged to post their thoughts on scientific or clinical advances they have heard about at the meeting, and on upcoming important challenges in human genetics, via ASHG's social media outlets (Twitter, Facebook).

Twitter: http://twitter.com/#!/geneticssociety, use hashtag #ASHG2012
Facebook: https://www.facebook.com/GeneticsSociety

You can also address your comments through Twitter directly to Chris Gunter, @girlscientist, during the meeting.

Posts by meeting participants will be followed and summarized at the beginning of the session by Chris Gunter, 2012 Program Committee Member.

After the brief presentations by the panelists there will be opportunities for audience members to ask questions of one or more panel members.

At the conclusion of the session, the moderator will provide a brief summary, and the meeting will be adjourned by the 2012 President, Mary-Claire King.

 

 


 

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