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Abstracts from the 53Rd European Society of Human Genetics (ESHG) Conference: Oral Presentations

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Abstracts from the 53Rd European Society of Human Genetics (ESHG) Conference: Oral Presentations European Journal of Human Genetics (2020) 28:1–140 https://doi.org/10.1038/s41431-020-00740-6 ABSTRACTS COLLECTION Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations © European Society of Human Genetics 2020. Modified from the conference website and published with permission 2020 Volume 28 | Supplement 1 Virtual Conference June 6–9, 2020 Sponsorship: Publication of this supplement was sponsored by the European Society of Human Genetics. All content was reviewed and approved by the ESHG Scientific Programme Committee, which held full responsibility for the abstract selections. 1234567890();,: 1234567890();,: Disclosure Information: In order to help readers form their own judgments of potential bias in published abstracts, authors are asked to declare any competing financial interests. Contributions of up to EUR 10 000.- (Ten thousand Euros, or equivalent value in kind) per year per company are considered “Modest”. Contributions above EUR 10 000.- per year are considered “Significant”. Presenting authors are indicated with asterisks in the contributor lists. Plenary Sessions somatic mutations affecting RNA splicing factors and tumorigenesis, the promise of correct mis-splicing for can- PL1 Opening Plenary cer therapy, and the recent creation of CRISPR/Cas-based technologies for conducting mRNA isoform-level genetic PL1.2 screens. RNA splicing defects in cancer R. K. Bradley: None. R. K. Bradley* PL2 What’s New? Highlight Session Fred Hutchinson Cancer Research Center, Seattle, WA, PL2.1 United States Evaluation of DNA methylation episignatures for diag- nosis and phenotype correlations in 42 Mendelian neu- Alternative RNA splicing, the process whereby a single rodevelopmental disorders gene can give rise to many different proteins, has long been known to be dysregulated in many cancers. Recent E. Aref-Eshghi1, J. Kerkhof1, V. Pedro2, Groupe DI France, studies have provided concrete genetic evidence that spli- M. Barat-Houari3, N. Ruiz-Pallares4, M. Alders5,M. cing dysregulation directly promotes cancer initiation Mannens5, P. Henneman5, R. C. Hennekam6, A. Ciolfi7,S. and progression. For example, genes encoding RNA spli- Pizzi7, M. Tartaglia7, P. M. Campeau8, J. Rousseau8,M.A. cing factors are recurrently mutated in both hematologic Levy1,2, L. Brick9, M. Kozenko9, T. B. Balci1,2,10,V.M. malignancies and solid tumors. However, uncovering the Siu1,2, A. Stuart1, M. Kadour1,11, J. Masters1,11,K. specific mechanisms by which these mutations promote Takano12, T. Kleefstra13,14, N. de Leeuw13,14, M. Field15,M. tumorigenesis has proven challenging. Here, I will discuss Shaw16, J. Gecz16,17, G. Merla18, P. J. Ainsworth1,2,H. recent progress in establishing functional links between Lin1,2, D. I. Rodenhiser2,19, M. J. Friez20, M. Tedder20,J.A. 2 J. del Picchia Lee20, B. R. DuPont20, R. E. Stevenson20, S. A. Skinner20, Conclusions: This study more than doubles the number C. E. Schwartz20, D. Genevieve4,21, B. Sadikovic1,2* of published syndromes with DNA methylation episigna- tures, and most significantly, opens new avenues for 1London Health Sciences Centre, London, ON, Canada, accurate diagnosis and clinical assessment in individuals 2Western University, London, ON, Canada, 3Universitaire de affected by these disorders. Montpellier, Montpellier, France, 4Centre Hospitalier Uni- E. Aref-Eshghi: None. J. Kerkhof: None. V. Pedro: None. versitaire de Montpellier, Montpellier, France, 5Amsterdam M. Barat-Houari: None. N. Ruiz-Pallares: None. M. Alders: University Medical Centers, Amsterdam, Netherlands, 6Uni- None. M. Mannens: None. P. Henneman: None. R. C. versity of Amsterdam, Amsterdam, Netherlands, 7Ospedale Hennekam: None. A. Ciolfi: None. S. Pizzi: None. M. Pediatrico Bambino Gesù, Rome, Italy, 8University of Tartaglia: None. P. M. Campeau: None. J. Rousseau: None. Montreal, Montreal, QC, Canada, 9McMaster University, M. A. Levy: None. L. Brick: None. M. Kozenko: None. T. Hamilton, ON, Canada, 10Lawson Health Research Institute, B. Balci: None. V. M. Siu: None. A. Stuart: None. M. London, ON, Canada, 11St. Joseph’s Health Care, London, Kadour: None. J. Masters: None. K. Takano: None. T. ON, Canada, 12Shinshu University Hospital, Nagano, Japan, Kleefstra: None. N. de Leeuw: None. M. Field: None. M. 13Radboud University Medical Center, Nijmegen, Nether- Shaw: None. J. Gecz: None. G. Merla: None. P. J. lands, 14Donders Center for Medical Neuroscience, Nijme- Ainsworth: None. H. Lin: None. D. I. Rodenhiser: None. gen, Netherlands, 15Hunter Genetics, Waratah, Australia, M. J. Friez: None. M. Tedder: None. J. A. Lee: None. B. R. 16The University of Adelaide, Adelaide, Australia, 17South DuPont: None. R. E. Stevenson: None. S. A. Skinner: Australian Health and Medical Research Institute, Adelaide, None. C. E. Schwartz: None. D. Genevieve: None. B. Australia, 18IRCCS-Casa Sollievo della Sofferenza, San Sadikovic: None. Giovanni Rotondo, Italy, 19Children’s Health Research Institute, London, ON, Canada, 20Greenwood Genetic Center, PL2.2 Greenwood, SC, United States, 21Montpellier University, Identity-by-descent detection across 487,409 British Montpellier, France samples reveals fine-scale population structure, evolu- tionary history, and trait associations Introduction: Genetic syndromes frequently present with overlapping clinical features and negative or ambiguous J. Nait Saada1*, G. Kalantzis1, D. Shyr2, M. Robinson3, genetic findings which can confound accurate diagnosis and A. Gusev4,5, P. Palamara1,6 clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA 1Department of Statistics, University of Oxford, Oxford, methylation patterns (episignatures). United Kingdom, 2Department of Biostatistics, Harvard T. Materials and Methods: Peripheral blood episignatures H Chan School of Public Health, Boston, MA, United can be used for diagnostic testing as well as for the States, 3Department of Computer Science, University of interpretation of ambiguous genetic test results. We present Oxford, Oxford, United Kingdom, 4Brigham & Women’s here an approach to episignature mapping of the largest Hospital, Division of Genetics, Boston, MA, United States, number of genetic syndromes studied to date (n = 42), which 5Department of Medical Oncology, Dana-Farber Cancer has allowed the identification of 34 robust disease-specific Institute, Boston, MA, United States, 6Wellcome Centre for episignatures. Human Genetics, University of Oxford, Oxford, United Results: We examine emerging patterns of overlap, as well Kingdom as similarities and hierarchical relationships across these episignatures to highlight their key features as related to The sharing of identical-by-descent (IBD) genomic seg- genetic heterogeneity, dosage effect, unaffected carrier status, ments is a key indicator of genetic relatedness between and incomplete penetrance. We demonstrate the necessity of individuals and plays an important role in a wide range of multiclass modeling for accurate genetic variant classification. genomic analyses. We developed a new method, called We demonstrate the utility of this tool in resolving ambiguous FastSMC, that enables accurate biobank-scale detection of clinical cases and identification of previously undiagnosed IBD segments transmitted by common ancestors living up cases through mass screening of a large cohort of subjects to several hundreds of generations in the past. FastSMC with developmental delays and congenital anomalies. Finally, combines a fast heuristic search for IBD segments with we outline and present early data from a Canadian national accurate coalescent-based likelihood calculations and esti- clinical trial EpiSign-CAN currently enrolling 4000 patients mates the age of common ancestors transmitting IBD to assess impact of this novel diagnostic technology on regions. We applied FastSMC to 487,409 phased samples diagnosis of neurodevelopmental conditions. from the UK Biobank and detected the presence of ~214 billion IBD segments transmitted by shared ancestors within Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: Oral Presentations 3 the past 1,500 years. We quantified time-dependent shared Translational Medicine, Federico II University, Naples, ancestry within and across 120 postcodes, obtaining a fine- Italy, 12Telethon Institute of Genetics and Medicine, grained picture of genetic relatedness within the past two Pozzuoli, Naples, Italy, 13Department of Psychiatry, millennia in the UK. Sharing of common ancestors strongly Donders Institute for Brain, Cognition and Behaviour, correlates with geographic distance, enabling us to localise Radboud University Medical Center, Nijmegen, Nether- a sample’s birth coordinates from genomic data with a lands, 14Karakter Child and Adolescent Psychiatry Center, median error of 44 km. We analysed genomic regions with Nijmegen, Netherlands, 15Department of Psychiatry and unusually high density of shared ancestry, which is indi- Behavioral Sciences and the MIND Institute, University of cative of recent positive selection, and detected 12 genome- California, Davis, Sacramento, CA, United States, wide significant signals, including 7 novel sites. We found 16Department of Clinical Genetics, Leiden University IBD sharing to be highly predictive of the sharing of ultra- Medical Center (LUMC), Leiden, Netherlands, 17Depart- rare variants in exome sequencing samples from the UK ment of Neurosciences, Biomedicine and Movement Biobank, enabling us to detect 29 associations (20 of which Sciences, University
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