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The 12th International Congress of Human Genetics and the American Society of Human Genetics 61st Annual Meeting October 11-15, 2011 Montreal, Canada PLATFORM ABSTRACTS Abstract/ Abstract/ Program Program Numbers Numbers Plenary Session Concurrent Platform Session C (51-60) Wednesday, October 12, 8:00 am – 10:00 am Friday, October 14, 4:15 pm – 6:15 pm SESSION 3 – Plenary Session on Epigenetics 1-2 SESSION 51 – Cancer Genetics II: Ovarian and Breast 163-170 These two abstracts were selected by the Scientific Program SESSION 52 – Genomics III: Genome Expression 171-178 Committee to be included in this invited plenary session with Douglas SESSION 53 – Molecular Basis III: Ciliopathies 179-186 Wallace and Emma Whitelaw. SESSION 54 – Statistical Genetics III: Analysis of 187-194 Sequence Data Concurrent Platform Sessions A (10-19) SESSION 55 – Epigenetics 195-202 Wednesday, October 12, 4:15 pm – 6:15 pm SESSION 56 – Complex Traits I: Approaches and Methods 203-210 SESSION 10 – Population Genetics 3-10 SESSION 57 – Cardiovascular Genetics II: Single Gene and 211-218 SESSION 11 – Genomics I: Structural Variation 11-18 Chromosomal Conditions SESSION 12 – Neurogenetics I: Autism 19-26 SESSION 58 – Neurogenetics III: Alzheimer, Parkinson and 219-226 SESSION 13 – Clinical Genetics I: Genotype-Phenotype 27-34 Neurodegenerative Diseases Correlation in Syndromes SESSION 59 – Clinical Genetics II: Neurodevelopmental 227-234 SESSION 14 – Chromosome Organization and Cancer 35-42 Disorders Cytogenetics SESSION 60 – Ethical, Legal, Social and Policy Issues 235-242 SESSION 15 – Genetic Testing and Counseling 43-50 SESSION 16 – Statistical Genetics I: Functional Consequences 51-58 Plenary Session of Genetic Variation Saturday, October 15, 10:15 am – 12:15 pm SESSION 17 – Molecular Basis I: Skin and Inflammatory 59-66 SESSION 67 – Plenary Session: Diseases, Populations and 242-244 Disorders Evolution: From the Cellular to the Continental SESSION 18 – Biochemical Genetics 67-74 These two abstracts were selected by the Scientific Program SESSION 19 – Cardiovascular Genetics I: Complex Traits 75-82 Committee to be included in this invited plenary session with Michael Stratton and Lalji Singh. Concurrent Platform Session B (30-39) Thursday, October 13, 10:15 am – 12:15 pm Concurrent Platform Session D (68-77) SESSION 30 – Molecular Basis II: Intellectual Disability 83-90 Saturday, October 15, 1:30 pm – 3:30 pm SESSION 31 – Statistical Genetics II: Expanding Genome-Wide 91-98 SESSION 68 – Clinical Genetics III: Copy Number Variants 245-252 Association Studies and Disease SESSION 32 – Evolutionary Genetics 99-106 SESSION 69 – Statistical Genetics IV: Rare Variants 253-260 SESSION 33 – Perinatal and Reproductive Genetics 107-114 SESSION 70 – Advances in Technology 261-268 SESSION 34 – Genomics II: Disease in Populations 115-122 SESSION 71 – Neurogenetics IV: Schizophrenia and Epilepsy 269-276 SESSION 35 – Cytogenetics 123-130 SESSION 72 – Complex Traits II: Genome-Wide Association 277-284 SESSION 36 – Cancer Genetics I: Melanoma and Leukemia 131-138 Studies SESSION 37 – Therapy for Genetic Disorders 139-146 SESSION 73 – Genomics IV: Disease and Chromatin 285-292 SESSION 38 – Pharmacogenomics 147-154 SESSION 74 – From Sequence to Function 293-300 SESSION 39 – Neurogenetics II: Paraplegia, Behavior and 155-162 SESSION 75 – Molecular Basis IV: Musculoskeletal Disorders 301-308 Migraine SESSION 76 – Genetic Screening and Education 309-316 SESSION 77 – Cancer Genetics III: Susceptibility to Outcome 317-324 Copyright © 2011 The American Society of Human Genetics. All rights reserved. T : 30917$COV1 08-27-11 10:27:54 Layout: 30917X : Start Odd Page 1 Platform Session 3: Plenary Session on Epigenetics 1 1 2 Identification of a mosaic activating mutation as the molecular basis Germline deletion of the miR-17~92 cluster causes developmental of Proteus syndrome using massively parallel sequencing of affected defects in human. J. Amiel1, E. Yao2, P. Callier3, L. Faivre3, V. Drouin4, tissues. L.G. Biesecker1, M.J. Lindhurst1, J.C. Sapp1, J.K. Teer1, J.J. John- S. Cariou1, A. Van Haeringen5, D. Genevieve6, A. Goldenberg4, M. Oufa- ston1, K. Peters1, J. Turner1, D. Bick2, L. Blakemore3, K. Brockman4, P. dem1, S. Manouvrier7, A. Munnich1, J. Alves Vidigal2, S. Lyonnet1, A. Hen- Calder5, M. Deardorff6, D.B. Everman7, R.M. Greenstein8, B.M. Kato9, K.M. rion-Caude1, A. Ventura2, L. de Pontual1. 1) Dept Genetics and INSERM Keppler-Noreuil10, R.T. Miyamoto11, K. Newman12, S. Rothenberg13, D.J. U781, Hosp Necker, Univ Paris 5, Paris, France; 2) Cancer Biology and Schwartzentruber14, V. Singhal15, J. Upton16, S. Wientroub17, E.H. Zackai7, Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, P.G. Robey18, P.L. Schwartzberg1, T.N. Darling19, L.L. Tosi3, J.C. Mullikin20. New York 10065, USA; 3) Service de Génétique, Hôpital d'enfants, Dijon, 1) NHGRI, NIH, Bethesda, MD, USA; 2) Division of Pediatric Genetics, France; 4) Service de Génétique, Hôpital Charles Nicolle, Rouen, France; Medical College of Wisconsin, Milwaukee, WI, USA; 3) Division of Orthopae- 5) Department of Human and Clinical Genetics, Leiden University Medical dics and Sports Medicine, Children's Hospital and Medical Center, Washing- Center, Leiden, The Netherlands; 6) Service de Génétique, Hôpital Arnaud ton, DC, USA; 4) Department of Pediatrics and Pediatric Neurology, Georg de Villeneuve, Montpellier, France; 7) Service de Génétique Clinique, Hôpital August University, Göttingen, Germany; 5) The Royal National Orthopaedic J. de Flandre, Lille, France. Hospital, Brockley Hill, Stanmore, London, UK; 6) Division of Human Genet- Oculodigitoesophagoduodenal syndrome (ODED, MIM164280) is an ics, Children's Hospital of Pennsylvania, Philadelphia, PA, USA; 7) Green- autosomal dominant syndrome with microcephaly, relative short stature and wood Genetics Center, Greenwood, SC, USA; 8) Department of Genetics digital anomalies as core features. ODED is caused by germline loss-of- and Developmental Biology, University of Connecticut, West Hartford, CT, function mutations of the MYCN gene (MIM 164840) at 2p24 and genetic USA; 9) The Ear Institute, Palm Desert, CA, USA; 10) University of Iowa, heterogeneity has been suspected. We performed a 244k CGH-array in 10 Department of Pediatrics, Division of Genetics, Iowa City, IA, USA; 11) index cases displaying skeletal abnormalities consistent with a diagnosed Department of Otolaryngology, Indiana University-Purdue University India- as ODED but lacking any mutation at the MYCN locus. We first identified napolis, Indianapolis, IN, USA; 12) Department of Surgery, Children's a 13q31.3 in 2 familial cases (with 2 and 3 affected individuals respectively), National Medical Center, Washington, DC, USA; 13) Department of Pediatric spanning 2.98 Mb to 165 kb with a shortest region of overlap encompassing Surgery, Rocky Mountain Hospital for Children, Denver, CO, USA; 14) Sur- miR-17~92 and the first exon of GPC5. No GPC5 coding sequence mutation gery Branch, National Cancer Institute, NIH, Bethesda, MD, USA; 15) could be identified in the remaining 8 cases. The DECIPHER Database Department of Pediatric Plastic and Craniofacial Surgery, Children's Mercy quoted an individual with a similar phenotype and harbouring a 180kb hemi- Hospitals and Clinics; Kansas city, MO, USA; 16) Department of Surgery, zygous 13q31.3 microdeletion encompassing the entire miR-17~92 locus Children's Hospital Boston, Boston, MA, USA; 17) Department of Pediatric and the first exon of GPC5. miR-17~92 is a polycistronic miRNA cluster, Orthopaedics, Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv also known as Oncomir-1, encoding for six distinct miRNAs essential for University, Tel Aviv, Israel; 18) NIDCR, NIH, Bethesda, MD, USA; 19) mammalian development. Indeed, its complete inactivation leads to perinatal Department of Dermatology, Uniformed Services University of the Health lethality in mice. Both MYC and MYCN can activate the transcription of miR- Sciences, Bethesda, MD, USA; 20) NIH Intramural Sequencing Center, 17~92 and can directly bind to the miR-17~92 promoter region in human Rockville,MD, USA. and murine cells. Mice carrying a heterozygous targeted deletion of miR- Proteus syndrome manifests mosaic overgrowth in skin, connective tissue, 17~92 are viable and fertile. We show that they recapitulate the ODED brain, and other tissues. It was hypothesized to be caused by a mosaic phenotype as they are smaller, microcephalic and present a striking shorten- mutation, lethal in the non-mosaic state. We tested this hypothesis using ing of the mesophalanx of the fifth ray of the upper limbs. Homozygous massively parallel sequencing of DNA from Proteus syndrome tissues, com- knock-out embryos show complete absence of the mesophalanx of the fifth paring affected to unaffected tissues. Seventeen samples from 11 patients digit, the presence of a small mesophalanx of the second digit, and hypopla- were sequenced using targeted exome capture. These samples included sia of the first digital ray. Neither syndactyly nor intestinal atresia was four affected-normal sample pairs, two affected samples from a fifth patient, observed. Importantly, GPC5 expression is similar in miR-17~92 mutant one pair of samples from discordant monozygotic twins, and five unaffected and control mice. Our results show that various aspects of mammalian parents. We generated ~1.6 Gb of sequence data, with >87% coverage of development via MYCN occur through transactivation of miR-17~92 (for exons with a high quality
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  • High-Throughput Discovery of Novel Developmental Phenotypes

    High-Throughput Discovery of Novel Developmental Phenotypes

    High-throughput discovery of novel developmental phenotypes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Dickinson, M. E., A. M. Flenniken, X. Ji, L. Teboul, M. D. Wong, J. K. White, T. F. Meehan, et al. 2016. “High-throughput discovery of novel developmental phenotypes.” Nature 537 (7621): 508-514. doi:10.1038/nature19356. http://dx.doi.org/10.1038/nature19356. Published Version doi:10.1038/nature19356 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071918 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2017 March 14. Published in final edited form as: Nature. 2016 September 22; 537(7621): 508–514. doi:10.1038/nature19356. High-throughput discovery of novel developmental phenotypes A full list of authors and affiliations appears at the end of the article. Abstract Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms #Corresponding author: [email protected].