European Journal of Human Genetics (2019) 27:748–869 https://doi.org/10.1038/s41431-019-0407-4 MEETING ABSTRACTS Abstracts from the 51st European Society of Human Genetics Conference: Oral Presentations © European Society of Human Genetics 2019 June 16–19, 2018, Fiera Milano Congressi, Milan Italy Sponsorship: Publication of this supplement is 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. 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 1234567890();,: 1234567890();,: "Modest". Contributions above EUR 10 000.- per year are considered "Significant". Plenary Sessions PL1 Opening plenary lecture T. Lappalainen: D. Speakers Bureau/Honoraria (speak- ers bureau, symposia, and expert witness); Modest; Merck. PL1.1 Leena Peltonen Lecturer - Complex Genetics PL1.2 Recent advances in mutational signatures of human cells T. Lappalainen1,2 S. Nik-Zainal 1New York Genome Center, New York, NY, United States, 2Columbia University, New York, NY, United States Department of Medical Genetics, Cambridge, United Kingdom Detailed characterization of cellular effects of genetic var- A cancer genome contains the historic mutagenic activity iants is essential for understanding biological processes that that has occurred throughout the development of a underlie genetic associations to disease, to improve the tumour. While driver mutations were the main focus of interpretation of the personal genome, and to characterize cancer research for a long time, passenger mutational the genetic architecture of molecular variation. This has signatures - the imprints of DNA damage and DNA repair inspired large consortium projects to create and integrate processes that have been operative during tumorigenesis - population-scale genome data with transcriptome data – as are also biologically informative. In this lecture, I provide well as other molecular phenotype data – in human popu- a synopsis of this concept, describe the insights that we lations. The catalogs of genetic effects on the transcriptome have gained through combinations of computational across multiple human tissues and conditions now allows analysis and experiments in cell-based systems, and downstream discovery in diverse questions in genetics, showcase how we have developed the concept into including joint effects of regulatory and coding variants applications that we hope to translate into clinical utility underlying modified penetrance of disease-causing variants, in the near future. and novel methods to understand variation in gene dosage S. Nik-Zainal: None. in human populations and patients. Abstracts from the 51st European Society of Human Genetics Conference: Oral. 749 PL2 What's New and Late Breaking Session P. Lacaze: F. Consultant/Advisory Board; Modest; BC Platforms. R. Sebra: A. Employment (full or part-time); PL2.1 Significant; Sema4. M. Riaz: None. R. Woods: None. Genomic sequencing 15,000 healthy elderly individuals - I. Winship: None. E. Schadt: A. Employment (full or part- Implications for clinical genetics time); Significant; Sema4. J. McNeil: None. P. Lacaze1, R. Sebra2, M. Riaz1, R. Woods3, I. Winship4,5, PL2.2 ASPREE Investigator Group, ASPREE Healthy Ageing CRISPR-QTL mapping as a genome-wide association Biobank, E. Schadt2, J. McNeil3 framework for cellular genetic screens of the noncoding genome 1Public Health Genomics, Monash University, Melbourne, Australia, 2Icahn Institute and Dept. of Genetics & Genomic M. Gasperini1, A. Hill1, J. L. McFaline Figueroa1, B. Martin1, Sciences at Mount Sinai School of Medicine, New York, NY, C. Trapnell1, N. Ahituv2, J. Shendure1,3,4 United States, 3School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia, 4Genetic 1University of Washington, Seattle, WA, United States, Medicine and Family Cancer Clinic, Royal Melbourne 2University of California San Francisco, San Francisco, CA, Hospital, Melbourne, Australia, 5Department of Medicine, United States, 3Brotman Baty Institute for Precision Medicine, University of Melbourne, Melbourne, Australia Seattle, WA, United States, 4Howard Hughes Medical Institute, Seattle, WA, United States Introduction: The variable penetrance of pathogenic var- iants remains a major challenge to clinical genetics practice, Almost all noncoding variants returned from whole genome particularly in predictive testing of hereditary cancer risk sequencing (WGS) cannot be confidently interpreted. genes. Ascertainment bias towards affected individuals and Although most are thought to disrupt gene function by their families has in part shaped our understanding of gene disrupting regulatory-elements such as enhancers, it is still penetrance. Here we report, for the first time, rates of largely unknown which noncoding regions constitute true pathogenic variation in hereditary cancer genes across enhancers, nor which genes each enhancer influences. To thousands of healthy elderly individuals, ascertained with- empirically address this, we have developed CRISPR-QTL out reference to clinical phenotype or family history, mapping, a framework in which large numbers of noncod- enrolled in an aspirin primary prevention trial. ing perturbations are introduced to each cell on an isogenic Materials and Methods: Individuals enrolled in the background, followed by single-cell RNA-sequencing ASPirin in Reducing Events in the Elderly (ASPREE) (scRNA-seq). This framework is borrowed from conven- Healthy Ageing Biobank were screened using a 760 gene tional human expression quantitative loci (eQTL) studies, ‘super-panel’ including pan-cancer gene coverage. The but with individual humans replaced by individual cells; average age was 75 years (min 65 years, max. 98 years), variants replaced by 'unlinked' combinations of guide RNA- and all participants were confirmed to be free of life- programmed perturbations per cell; and tissue-level RNA- threatening cancer diagnoses, cardiovascular disease or seq of many individuals replaced by scRNA-seq of many cognitive decline at time of enrolment. Medical records, cells. We applied CRISPR-QTL mapping to evaluate 1,119 family history and clinical data were mined for evidence of candidate enhancers with no strong a priori hypothesis as to cancer phenotypes in mutation carriers. their target gene(s). Perturbations were made by a nuclease- Results: We detected hundreds of pathogenic and high- dead Cas9 tethered to KRAB, and introduced at a mean confidence predicted-deleterious mutations in hereditary ‘allele frequency’ of 1.1% into a population of 47,650 cancer genes in elderly individuals (>10,000 samples profiled human K562 cells (median of 15 gRNAs identified sequenced Feb 2018). Mutations were often detected in per cell). We tested for differential expression of all genes the absence of any reported disease phenotype or family within 1 megabase of each candidate enhancer, evaluating history. Overall, pathogenic variants were found at a 17,584 potential enhancer-target gene relationships in one comparable rate to population-based cohorts, suggesting experiment. We identify 128 cis CRISPR-QTLs whose over-representation of non-penetrant individuals in targeting resulted in downregulation of 105 nearby genes this study. (of which 49 genes are thought to underlie disease). We Conclusions: Pathogenic germline mutations in cancer anticipate that the power of CRISPR-QTL mapping will predisposition genes may exist more commonly in the facilitate the comprehensive characterization of enhancer- population than expected, raising questions about clinical gene relationships, thus advancing interpretation of non- actionability, risk and penetrance. coding variants discovered through WGS. 750 J. del Picchia M. Gasperini: None. A. Hill: None. J.L. McFaline A. Munnich1, D. Papy-Garcia2, M. De La Dure-Molla1, Figueroa: None. B. Martin: None. C. Trapnell: None. V. Cormier-Daire1 N. Ahituv: None. J. Shendure: None. 1Institut Imagine INSERM U1163, Paris, France, 2CRRET PL2.3 Laboratory, Université Paris-Est Créteil, Créteil, France, Elimination of aneuploid cells in the early mammalian 3Polygene AG, Rümlang, Switzerland, 4Cerrahpasa Medicine embryo School, Istanbul, Turkey, 5Akdeniz University Facultu of Medecine, Antalya, Turkey, 6Medical University of Innsbruck, S. Singla, M. Zernicka-Goetz Innsbruck, Austria, 7University Medical Center Groningen, Groningen, Netherlands, 8Center for Molecular Medecine, University of Cambridge, Cambridge, United Kingdom Utrecht, Netherlands, 9University Medical Center Utrecht, Utrecht, Netherlands, 10Radboud University Medical Center, Whole chromosomal aneuploidies - loss and/or gain of Nijmegen, Netherlands, 11Hôpital Bichat, Paris, France chromosomes from a euploid complement - are responsible for the low fecundity in humans. Here we use mouse Skeletal dysplasias with multiple dislocations are a group of embryo as a model system to understand how severe disorders characterized by dislocations of large joints, mosaic aneuploidy affects embryonic development. To scoliosis, short stature and a variable combination of cleft experimentally induce chromosome missegregation in the palate, heart defects, intellectual disability and obesity. With cleavage stage embryos, we inhibit