American Society of Human Genetics 63rd Annual Meeting October 22–26, 2013 Boston PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Tuesday 31 Advances and References in Genomic Technology Room 210 #196–#204 2. Plenary Abstract Presentations Hall B2 #1–#6 32 Genetic Testing for Neurodevelopmental Disease: Wednesday Genotype: Phenotype Challenges Room 205 #205–#213 2:00pm–4:15pm: Concurrent Platform Session A (10–18): 33 Gene Regulation—At a Multitude of 10. Which Comes First: The Sequence or Levels Room 253 #214–#222 the Biology? Hall B2 #7–#15 34 Cardiovascular Genetics: Exome 11 The Shifting Landscape of Genetic Sequencing and Animal Models Room 258 #223–#231 Testing: Approaches and Success 35 Genomic Medicine: Counseling, Stories Grand Education and Health Services Westin Hotel, Ballroom East #16–#24 Grand 12 Methods in Statistical Genetics Grand Ballroom AB #232–#240 Ballroom West #25–#33 36 Biochemical and Clinical 13 Genetic Variation in Gene Expression Room 210 #34–#42 Consequences of Mitochondrial 14 Cancer Epidemiology: New Loci and Dysfunction Westin Hotel, Methods Room 205 #43–#51 Grand 15 Psychiatric Disease: GWAS to Genes Room 253 #52–#60 Ballroom CDE #241–#249 16 Expanding Knowledge of Mendelian Disorders: Genes, Phenotypes & Friday Treatment Room 258 #61–#69 8:00am–10:15am:oncurrent Platform Session D (45–53): 17 Structural;shCopy Number Variation 45 Mo' Data, Mo' Problems? Hall B2 #250–#258 and Disease Westin Hotel, 46 Cancer Genomics Grand Grand Ballroom East #259–#267 Ballroom AB #70–#78 47 Demography In and Out of Africa Grand 18 Inborn Errors of Metabolism: From Ballroom West #268–#276 Identification to Treatment Westin Hotel, 48 Fine-Mapping and Function of Grand Candidate Loci Room 210 #277–#285 Ballroom CDE #79–#87 49 New Genes and Disorders Room 205 #286–#294 50 Neurodegenerative Disease and the Thursday Aging Brain Room 253 #295–#303 8:00am–10:15am: Concurrent Platform Session B (19–27): 51 Epigenetics: From Genomes to Genes Room 258 #304–#312 19 Hereditary Cancer Syndromes Hall B2 #88–#96 52 New Frontiers in Pharmacogenetics Westin Hotel, 20 Variants, Variants Everywhere Grand Grand Ballroom East #97–#105 Ballroom AB #313–#321 21 Genetic Epidemiology: Applications and 53 Genomic Approaches for Study of Rare Methods Grand Neurogenetic Disorders Westin Hotel, Ballroom West #106–#114 Grand 22 Cardiovascular Genetics: Gene Ballroom CDE #322–#330 Discovery through GWAS and Sequencing Room 210 #115–#123 Friday 23 From eQTLs to Epigenetics and 2:00pm–4:15pm: Concurrent Platform Session E (54–62): Beyond Room 205 #124–#132 54 Hundreds of New GWAS Loci Hall B2 #331–#339 24 Neurogenetics: Illuminating 55 Impact of Bottlenecks and Population Mechanisms Room 253 #133–#141 Growth on Rare Variation Grand 25 Genetic Interactions in Complex Traits Room 258 #142–#150 Ballroom East #340–#348 26 Advances in the Genetics of Skeletal 56 Haplotypes, Imputation and InteractionsGrand and Morphologic Disorders Westin Hotel, Ballroom West #349–#357 Grand 57 Autism and Neurodevelopmental Ballroom AB #151–#159 Disorders Room 210 #358–#366 27 Causes and Consequences of 58 Cardiovascular Genetics: Functional Chromosomal Variations Westin Hotel, Characterization and Clinical Grand Applications Room 205 #367–#375 Ballroom CDE #160–#168 59 Prenatal and Reproductive Genetics Room 253 #376–#384 60 Ethical, Legal, Social and Policy Issues Room 258 #385–#393 Thursday 61 Genomics of Developmental Disorders Westin Hotel, 2:00pm–4:15pm: Concurrent Platform Session C (28–36): Grand 28 Low Frequency Variants for Complex Ballroom AB #394–#402 Traits Hall B2 #169–#177 62 Prostate and GI Cancer Susceptibility Westin Hotel, 29 Selection, Demography and Functional Grand Polymorphism Grand Ballroom CDE #403–#411 Ballroom East #178–#186 30 Statistical Methods for Family Data Grand Ballroom West #187–#195 Copyright © 2013 The American Society of Human Genetics. All rights reserved. X : 46025APLCV 09-12-13 23:24:13 Layout: 30917X : Start Odd Page 1 ASHG 2013 Abstracts 1 1 3 Whole exome sequencing of 94 matched brain metastases and paired Chromatin loops and CNVs: the complex spatial organization of the primary tumors reveals patterns of clonal evolution and selection of 16p11.2 locus. M.N. Loviglio1, M. Leleu2, N. Ghedolf1, E. Migliavacca1, K. driver mutations. S.L. Carter1, P.K. Brastianos2,3, S. Santagata4, A. Taylor- Männik1, J.S. Beckmann3, 4, S. Jacquemont3, J. Rougemont2, A. Reymond1. Weiner 1, P. Horowitz 4, K. Ligon 4, J. Seaone 5, E. Martinez-Saez 5, J. 1) Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, Tabernero5, D. Cahill3, S. Paek6, I. Dunn4, B. Johnson2, M. Rabin2, N.U. Switzerland; 2) EPFL, Lausanne, Switzerland; 3) Service de Génétique Lin2, R. Jones2, P. Hummelen2, A. Stemmer-Rachamimov3, D.L. Louis3, Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; T.T. Batchelor3, J. Baselga7, R. Beroukhim2, G. Getz1,3, W.C. Hahn2. 1) 4) Swiss Institute of Bioinformatics, Lausanne, Switzerland. Cancer genome analysis, Broad institute, Cambridge, MA; 2) Dana-Farber Hemizygosity of the 16p11.2 ~600kb BP4-BP5 region (29.5 to 30.1Mb) is Cancer Institute, Boston, MA; 3) Massachusetts General Hospital, Boston, one of the most frequent known genetic etiologies of autism spectrum disor- MA; 4) Brigham and Women's Hospital; 5) Vall D’Hebron University Hospital; der (ASD). It is also associated with a highly penetrant form of obesity 6) Seoul National University College of Medicine; 7) Memorial Sloan-Ketter- and a significant increase in head circumference. Mirror phenotypes are ing Cancer Center. observed in carriers of the reciprocal duplication, who present a high risk of Cancer metastasis to the brain is the most common malignancy of the being underweight, microcephalic and/or schizophrenic. The distal 16p11.2 brain, affecting approximately 200,000 patients per year. Brain metastases 220kb BP2-BP3 deletion is similarly associated with obesity and neuropsy- are associated with high morbidity and mortality, with a median survival time chiatric disorders. We assessed possible chromatin interplays between of 3–4 months. Despite the high incidence, relatively little is known about these regions via long-range acting regulatory elements using high-resolu- the molecular mechanisms driving brain metastasis. We subjected 94 trios tion Chromosome Conformation Capture Sequencing (4C-seq) technology. consisting of primary tumor, brain metastasis, and normal reference tissue We compared the three dimensional organization at the 16p11.2 locus to whole exome sequencing (WES). To analyze the data, we developed between normal copy number and 600kb deletion or duplication state using novel computational tools to derive high quality allelic copy-number profiles the promoters of the SH2B1, MVP, KCTD13, ALDOA, TBX6 and MAPK3 directly from the WES data. These were used to perform an integrative genes as “viewpoints”. The analysis of normal copy number samples high- analysis of somatic copy-number alterations (SCNAs) and somatic single lights complex chromatin looping between genes located in the 600kb and nucleotide variants (SSNVs). This analysis allowed us to estimate the clonal 220kb regions. In particular, blocks of regulators in chromosomal kontext architecture of the primary and metastatic samples from each patient, and of the 5 viewpoints from the 600kb interval encompass the genes CD19, to reconstruct a single phylogenetic tree relating all of the subclones in both LAT, RABEP2, TUFM and SH2B1, whose polymorphisms and mutations samples. Every metastasis developed from a single clone, consistent with were previously associated with BMI, serum leptin, maladaptive behaviors a single cell of origin. In some cases, we determined that the primary sample and obesity. This interaction was reciprocally confirmed using SH2B1 as a represented an ancestral population with respect to the metastases, based viewpoint. To gauge whether the presence of a genomic rearrangement on the presence of subclones present in the primary that became fully clonal alters any of the identified chromatin interactions along chromosome 16, in the metastasis. In other cases, we observed fully clonal mutations in the we compared interaction profile signals of deletions and duplications of primary sample that were not present in the metastasis, indicating a sibling the 600kb BP4-BP5 region and of controls. Considering all viewpoints we relationship between the two samples. Subclonal mutations in the metastasis identified 342 and 378 regions whose looping intensities are significantly by definition occurred within the brain; these mutations displayed different modified in deleted and duplicated samples, respectively. In parallel, we mutational signatures than those acquired in the primary tumor. These profiled the transcriptome of lymphoblastoid cell lines of 50 600kb BP4-BP5 contrasts were most pronounced in cases of lung cancer or melanoma, with deletion, 32 reciprocal duplication and 29 control individuals and identified tobacco and UV signatures prominent in these primaries and nearly absent 1188 differentially expressed (DE) genes using a numerical variable to reflect from the mutations acquired after metastasis. In order to understand the a dosage effect. 27 of the 74 DE genes (36.5%) mapping on chromosome molecular drivers of clonal evolution and metastasis in our data, we anno- 16 show concomitant significant changes in chromatin interaction. Our tated each subclone with driver mutations identified using large numbers of results show that