European Journal of Human Genetics (2019) 26:3–112 https://doi.org/10.1038/s41431-018-0249-5 ABSTRACT Abstracts from the 50th European Society of Human Genetics Conference: Oral Presentations Copenhagen, Denmark, May 27–30, 2017 Published online: 1 October 2018 © European Society of Human Genetics 2018 The ESHG 2017 marks the 50th Anniversary of the first ESHG Conference which took place in Copenhagen in 1967. Additional information about the event may be found on the conference website: https://2017.eshg.org/ Sponsorship: Publication of this supplement is sponsored by the European Society of Human Genetics. All authors were asked to address any potential bias in their presentation and to declare any competing financial interests. These disclosures are listed at the end of each presentation. 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". Plenary Sessions By 1988 it had become clear that something more was needed if the ESHG was to become a significant force in 1234567890();,: 1234567890();,: developing a European human genetics community. Revo- PL1 lutionary moves culminated at the meeting in Leuven in 50 years of ESHG 1991 where a rotating president and officers were elected, and statutes adopted formally incorporating the society PL1.1 under Belgian law. The society’s journal, the European A brief history of how we got here Journal of Human Genetics, was established shortly after- wards and the modern ESHG was born. We now have an A. Read annual turnover of over 2 million euros, professional administration through Jerome del Picchia and his team at Manchester, United Kingdom the Vienna Medical Academy, and an important voice in European and international developments in human genet- This year the European Society of Human Genetics ics. Jan Mohr (who died in 2009) might have mixed feelings celebrates the 50th anniversary of its first meeting, held here about some of these developments but surely he would in Copenhagen in 1967. I have been asked, on behalf of the agree that this 2017 meeting is the best human genetics Board and Executive of the Society, to start off this year’s conference ever. conference with a brief look back at how we came to be here. In doing this I have drawn heavily on the historical A. Read: None. material assembled by Professor Peter Harper, whose arti- cles should be consulted for more detail. PL1.2 The story of the ESHG is a story of two halves. The first How will the present time in genetics be 24 years, up to 1991, were dominated by one man, Professor remembered? Jan Mohr of Copenhagen. When he agreed with a small group of colleagues to start a European Society of Human H. Brunner1,2 Genetics his vision was of a stripped-down organisation with minimal administrative tasks. There were no elected officers, 1Department of Human Genetics Radboud UMC, Nijmegen, just a permanent secretary (himself for all those years) and Netherlands, 2Dept of Clinical Genetics, Maastricht UMC, an unchanging 20-member Board. Virtually their only Maastricht, Netherlands function was to nominate somebody each year to organise a symposium on some aspect of human genetics. The society At 50 years, the Society of Human Genetics has con- gave no financial support for this - it hardly could, with only fidently assumed its current position as a pillar of modern around 200 members whose subscription was $7. medicine. Is ours a special time? Have we reached the 4 high-point of Human Genetics? I don’t think that the techniques for mosaic situations, long read sequencing for history of human genetics ends here at all. Rather, it repetitive elements and other genomic dark matter, and seems that fundamental change is still very much in the whole genome sequencing to capture smaller genomic air. First, let’s celebrate that after more than 100 years, the rearrangements. All of these will come. Still, reading the battle between the Mendelians and Biometricians has genome does not equal understanding it. Fortunately, finally ended. And it is a draw. Mendelian rare conditions Functional Genomics is about to come of age, now that mainly reflect gene disruptions subject to strong selective the groundwork has been done with the Hapmap, forces, whereas common complex disease largely reflects ENCODE and Blueprint projects. The future of Human common polygenic regulatory variation of gene activity. Genomics will be radically different as we start to study Sometimes these mix, as for the major neurodevelop- Traits rather than States, and this at the single cell level mental disorders: Intellectual disability, Autism, and and in real time. Multi-omics approaches will arrive soon, Schizophrenia are mostly due to a mix of polygenic and as will innovative gene therapy approaches. The future de novo single gene variants. The Mendelian forms being may turn out much more surprising and informative than associated with lower IQ. As Galton predicted in the 19th any of us can now predict. century, height is generally polygenic and Peter Vis- scher’s work has used this data to show that most of the H. Brunner: None. heritability is not missing but undetected, because the effects of individual loci are too small to pass stringent PL1.3 significance tests. Work from Sardinia shows that some of The Future: Solved Problems and Persisting the alleles that confer short stature affect known Mende- Challenges lian genes, which have drifted up to appreciable fre- quencies in this population to create the well-known A. Visel1,2,3 island effect on height. After a period of frenzied activity following the invention of next generation sequencing, the 1Lawrence Berkeley National Laboratory, Berkeley, CA, era of monogenic disease gene discovery has passed its United States, 2DOE Joint Genome Institute, Walnut Creek, peak. At the same time, our ability to see pathogenic CA, United States, 3University of California, Merced, CA, variation rather than infer it, is fundamentally changing United States medicine and our societies. Rare diseases have become a recognized part of medicine, not just curiosities. One such Groundbreaking discoveries by individual researchers, area where gene-based discoveries are changing medicine disruptive technological advancements, and massive-scale fast is cancer therapy. The understanding of the gene data collection efforts by large research consortia have composition of the Philadelphia chromosome led to the fundamentally transformed the field of human genetics. The first targeted cancer drug, Imatinib. Other examples fol- introduction of powerful data generation and analysis lowed such as EGFR mutations in lung cancer. Soon, all techniques fueled the emergence and rapid growth of the womenwithbreastandovariancancerwillbetestedfor field of genomics as a data-driven science. Researchers now BRCA1 and BRCA2 mutations, to guide their therapy. routinely apply genomic approaches to resolve the genetic Similar testing could happen for male patients with basis of human diseases in ways that were unimaginable prostate cancer. All this will lead to an enormous increase just a few decades ago. Extrapolating from the mind- in the detection of people with genetic predisposition for boggling pace of progress to date, I will attempt to speculate cancers, which constitutes an interesting example of how about the future of human genetics and genomics in the Molecular Pathology and Mendelian predisposition decades ahead. Specifically, I will discuss ways in which genetics come together. Work by Ségolene Ayme and many current challenges will likely become resolved others has led to the recent launch of the European through foreseeable technological improvements. More Reference Networks whose purpose is to improve diag- importantly, I will describe problems that are expected to nosisandcareforrarediseasespatientsacrossEurope. present persistent conceptual challenges. In particular, I will NIPT represents another major triumph for the power of discuss the continued conquest to decipher the vast non- next generation sequencing technology. It is almost coding portion of the human genome, our current difficul- incomprehensible how NIPT seemed such a distant goal ties in understanding its function, and barriers to identifying for so many years. The diagnostic rate of exome connections between non-coding sequence changes and sequencing and microarrays is between 20 and 60% for human disease. most diagnostic situations where Mendelian disease is sought. This experience underlines that the genome is not A. Visel: None. entirely readable yet. Progress requires single cell Abstracts from the 50th European Society of Human Genetics Conference: Oral. 5 PL2 E. Klopocki: None. D.G. Lupiáñez: None. S. Mundlos: What’s New? Highlights Session None. PL2.1 PL2.2 Enhancer composition and dosage control Quantifying the impact of rare coding variation developmental gene expression across the phenotypic spectrum A. J. Will1,2, G. Cova1,2, M. Osterwalder3, W. Chan1,2, N. Brieske1, A. Ganna1, F. K. Satterstrom1, S. Zekavat1, I. Das2, J. Alfoldi1,M.I. A. Visel3, E. Klopocki4, D. G. Lupiáñez1,2, S. Mundlos1,2 Kurki1, W. K. Thompson3, A. Byrnes1, K. J. Karczewski1, M. A. Rivas4, C. Churchhouse1, J. Flannick1, D. MacArthur1, M. J. Daly1,P.F. 1Max Planck Institute for Molecular Genetics, RG Devel- Sullivan5, J. C. Florez1, A. Palotie6, A. E. Locke7, A. Børglum8, opment and Disease, Berlin, Germany, 2Institute for Med- S. Kathiresan1, B. M. Neale1 ical