Title: Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: Oral Presentations
Abstract: C14 Late Breaking AbstractsC14.1 Progressive liver, kidney and heart degeneration in adults affected by TULP3 mutationsElisabeth Ott1, John Devane1, Eric G. Olinger2, Daniel Epting1, Eva Decker3, Anja Friedrich3, Nadine Bachmann3, Gina Renschler3, Tobias Eisenberger3, Genomics England Research Consortium4, Inga Gruenewald5, Martin Konrad6, Jens König6, Bernhard Schlevogt7, John Sayer8, Carsten Bergmann 1;3 1Department of Medicine IV, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany; 2Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom; 3Medizinische Genetik Mainz, Mainz, Germany; 4Genomics England Research Consortium, London, Germany; 5Institute for Pathology, University Hospital Münster, Münster, Germany; 6Department of General Pediatrics, University Hospital Münster, Münster, Germany; 7Department of Internal Medicine B, Gastroenterology, University Hospital Münster, Münster, Germany; 8Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom Background/Objectives: Organ fibrosis is an endpoint of many diseases. Ciliopathies usually start early in life and represent a considerable disease burden in paediatric patients. Methods: We performed NGS, clinical, imaging and histopathological analysis involving eight unrelated families. Mechanistic studies were conducted using patient liver, heart and kidney biopsies, a vertebrate model and patient cells. Results: We detected biallelic deleterious variants in TULP3, a critical adapter protein for ciliary trafficking, in 15 patients who presented with progressive degenerative disease in different organs including fibrocystic kidney disease, liver fibrosis and hypertrophic cardiomyopathy. Liver biopsies revealed a distinct fibrotic pattern not in line with ductal plate malformation usually seen in paediatric ciliopathies and myocardial fibrosis followed an atypical pattern reminiscent of systemic disease with cardiac involvement. We recapitulated the human phenotype in zebrafish as a vertebrate model and confirmed disruption of ciliary cargo composition in patient-derived primary cells. Additionally, we validated a novel interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis. Increased levels of DNA damage were also seen in patient cells. Patient-cell based transcriptomic studies highlighted the upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy, WNT and TGFß signalling. Conclusion: These findings identify a novel monogenic cause for progressive degenerative disease of major organs in which patients benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for well-balancing DNA-damage repair and tissue maintenance will help guiding novel therapeutic avenues for this and similar genetic and non-genomic diseases. References: Grants: DFG BE3910/9-1, SFB1453, BMBF 01GM1903. Conflict of Interest: Elisabeth Ott The authors declare no competing interests., John Devane The authors declare no competing interests., Eric G. Olinger The authors declare no competing interests., Daniel Epting The authors declare no competing interests., Eva Decker Full time employment at Medizinische Genetik Mainz.The authors declare no competing interests., Anja Friedrich Full time employment at Medizinische Genetik Mainz.The authors declare no competing interests., Nadine Bachmann Full time employment at Medizinische Genetik Mainz.The authors declare no competing interests., Gina Renschler Full time employment at Medizinische Genetik Mainz.The authors declare no competing interests., Tobias Eisenberger Full time employment at Medizinische Genetik Mainz.The authors declare no competing interests., Genomics England Research Consortium: None declared, Inga Gruenewald The authors declare no competing interests., Martin Konrad The authors declare no competing interests., Jens König The authors declare no competing interests., Bernhard Schlevogt The authors declare no competing interests., John Sayer The authors declare no competing interests., Carsten Bergmann The authors declare no competing interests. Carsten Bergmann holds a part-time faculty appointment at the University of Freiburg in addition to the Medizinische Genetik Mainz and his employment with the Limbach Group for which he heads and manages Limbach Genetics GmbH., His research lab receives support from the Deutsche Forschungsgemeinschaft (DFG) (BE 3910/8-1, BE 3910/9-1 and Collaborative Research Center SFB 1453) and the Federal Ministry of Education and Research (BMBF, 01GM1903I and 01GM1903G). C14.2 Random glucose GWAS trans-ethnic meta-analysis in almost half a million individuals provides insights into diabetes pathophysiology, complications and treatment stratificationVasiliki Lagou1, Longda Jiang2, Anna Ulrich3, Liudmila Zudina3, Zhanna Balkhiyarova3, Alessia Faggian3, Jared Maina4, Giuseppe Deganutti5, Ayse Demirkan3, Christopher Reynolds5, Marika Kaakinen3, Ben Jones6, Inga Prokopenko 3;4, the MAGIC investigators7 1Wellcome Sanger Institute, Hinxton, United Kingdom; 2The University of Queensland, Brisbane, Australia; 3University of Surrey, Clinical and Experimental Medicine, Guildford, United Kingdom; 4Institut Pasteur de Lille, CNRS, University of Lille, UMR 8199 - EGID, Lille, France; 5Coventry University, Centre for Sport, Exercise and Life Sciences, Coventry, United Kingdom; 6Imperial College London, Section of Endocrinology and Investigative Medicine, London, United Kingdom; 7Meta-Analysis of Glucose and Insulin-related Traits Consortium, https://magicinvestigators.org, United Kingdom Background/Objectives: Conventional measurements of fasting/postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on "around the clock" glucoregulatory processes. We performed GWAS meta-analysis of glucose measurements under non-standardised conditions (random glucose; RG) in 493,036 individuals of diverse ethnicities and without diabetes, enabling powerful locus discovery and innovative pathophysiological observations. Methods: We dissected associations (additive genetic model) between HRC-imputed DNA variants and RG, adjusted for age/sex/population structure, time since last meal (where available) in 17 studies, including UK Biobank. We investigated RG genetic (LD score regression/PRSs/hierarchical clustering) and causal (MR-Base) relationships with other phenotypes, and gene expression (metaXscan, DEPICT). Results: We discovered 142 RG loci (185 distinct signals), including 84 novel signals for glycaemia, 14 with sex-dimorphic effects, 9 identified through trans-ethnic analysis and 25 low/rare frequency signals. Regulatory, glycosylation, and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of gastrointestinal tract in the control of blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in GLP1R, a type 2 diabetes (T2D) treatment target, reveal that optimal selection of GLP-1R agonist therapy in the clinic will benefit from a tailored genetic stratification. We provide novel compelling evidence from Mendelian randomisation, that lung function is modulated by blood glucose levels (βMR-RG = -0.61, P = 3.5 × 10-4; βMR-T2D = -0.062, P = 1.42 × 10-21), and settle the longstanding controversy that pulmonary dysfunction is a diabetes complication. Conclusion: Our investigation yields wide-ranging insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification. References: Grants: H2020-SC1-HBC-28-2019-LONGITOOLS, WCRF-2017/1641, Diabetes UK(BDA number:20/0006307), PreciDIAB(ANR-18-IBHU-0001). Conflict of Interest: None declared. C14.3 Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders Wolfram Höps 1, David Porubsky2, Hufsah Ashraf3, PingHsun Hsieh2, Bernardo Rodriguez-Martin1, Feyza Yilmaz4, Jana Ebler3, Pille Hallast4, Flavia Maggiolini5;6, William Harvey2, Barbara Henning2, Peter Audano4, David Gordon2;7, Peter Ebert3, Patrick Hasenfeld1, Eva Benito1, Qihui Zhu4, Charles Lee4, Francesca Antonacci5, Matthias Steinrücken8;9, Christine Beck4;10, Ashley Sanders11;12;13, Tobias Marschall3, Evan Eichler2;7, Jan Korbel1;14 1European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; 2University of Washington School of Medicine, Seattle, United States; 3Heinrich Heine University Düsseldorf, Düsseldorf, Germany; 4The Jackson Laboratory For Genomic Medicine, Farmington, United States; 5University of Bari Aldo Moro, Bari, Italy; 6Consiglio per la Ricerca in Agricoltura e l'Analisi dell'Economia Agraria, Turi, Italy; 7Howard Hughes Medical Institute, Seattle, United States; 8The University of Chicago Department of Human Genetics, Chicago, United States; 9The University of Chicago Department of Ecology and Evolution, Chicago, United States; 10University of Connecticut Health Center, Farmington, United States; 11Max Delbrück Center for Molecular Medicine, Berlin, Germany; 12Berlin Institute of Health, Berlin, Germany; 13Charite Berlin, Berlin, Germany; 14European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom Background/Objectives: Inversions remain an understudied class of genetic variation, whose discovery has been challenging due to the frequent presence of large segmental duplications (SDs) at their flanks. Likewise, although some inversions can recurrently toggle between a direct and inverted state, the frequency of inversion recurrence and its association with genomic disorders has remained largely unexplored. Methods: Within the framework of the Human Genome Structural Variation Consortium, we integrated multiple genomic technologies, including Strand-Seq, Bionano optical mapping and long read assemblies, to accurately detect inversions in a haplotype-resolved manner. Recurrent inversions were distinguished from 'single' events using complementary population genetics approaches. Results: We discover 729 inversion loci genotyped across 41 diverse human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1 retrotransposition. Balanced inversions show an excess of common variants, and 72% are flanked by SDs or retrotransposons. We present evidence for inversion recurrence in 40 loci, encompassing 0.6% of the human genome, and with a bias towards sex-chromosomes. In addition, our analysis associates inversion recurrence with predisposition to chromosomal instability and genomic disorders, including microdeletions at the disease relevant 3q29, 15q13.3 and Williams syndrome regions. Conclusion: A comprehensive analysis of inversions in human genomes has unveiled widespread inversion recurrence and establishes a link to genetic instability and disease. References: Grants: National Institutes of Health (U24HG007497, U01HG010973, R01HG002385, R01HG010169), German Ministry for R&D (BMBF 031L0184), German Research Foundation (DFG 391137747), German Human Genome-Phenome Archive (DFG (NFDI 1/1)). Conflict of Interest: None declared. C14.4 Genetic basis of right and left ventricular heart shape Richard Burns 1, Julia Ramírez2, William Young2, Catrin Sohrabi2, Nay Aung3;4, Steffen Petersen3;4;5;6, Alistair Young1, Patricia Munroe2;4 1King's College London, London, United Kingdom; 2Queen Mary University of London, London, United Kingdom; 3William Harvey Research Institute, London, United Kingdom; 4Barts Health NHS Trust, London, United Kingdom; 5Health Data Research UK, London, United Kingdom; 6The Alan Turing Institute, London, United Kingdom Background/Objectives: Heart shape is a cardiovascular trait that captures variation in cardiac structure and is poorly represented by traditional phenotypes, demonstrating stronger relationships with cardiac disease risk factors (e.g., wall thickness, concentricity) and disease, and its genetic basis has not been studied. Methods: Automated analysis of cardiovascular magnetic resonance (CMR) images was performed in 45,683 participants in the UK Biobank to construct a heart shape atlas from right and left ventricular end-diastolic surface mesh models. The first ten principal components (PCs) of the atlas were defined as phenotypes, accounting for 82.5% of the total shape variance. We performed genome-wide association studies (GWAS) and identified 43 loci across the ten PCs. Results: Thirteen loci have not previously been reported with any ventricular structure, function, electrocardiogram (ECG) or cardiac disease traits. Bioinformatics analyses collated 63 candidate genes from eQTL, Hi-C and S-PREDIXCAN analyses alongside literature review. For PC4 which is associated with right ventricular conicity, we discovered 8 loci (5 are novel). Two candidate genes at these novel loci are TSPAN12 and TBX18 and MGI knockout model models demonstrate blood vessel abnormalities. Pathway analysis in g:Profiler including all candidate genes indicates significant enrichment in heart development, contraction and functional regulation process GO terms (p = 2.04E-9, 7.73E-8, 7.85E-8). Heritability estimates of the PCs ranged 8.5-36.3%, and lead/independent secondary variants identified in this study explain 0.8 – 3.9% of their variance. Conclusion: By characterising the genetics of heart shape, we have identified new candidate genes and explore the biological pathways implicated in defining cardiac shape. References: Grants: Conflict of Interest: None declared. C14.5 Noninvasive Prentatal Test results indicative of maternal malignancies: a nationwide genetic and clinical follow-up study Catharina Heesterbeek 1, Sietse Aukema2, Robert-Jan Galjaard3, Elles Boon4, Malgorzata Srebniak3, Katelijne Bouman5, Brigitte H.W. Faas6, Lutgarde C.P. Govaerts3, Mariette Hoffer7, Nicolette Den Hollander7, Klaske D. Lichtenbelt8, Merel C. van Maarle4, Lisanne van Prooyen Schuurman3, Maartje C. van Rij6, Heleen Schuring-Blom8, Servi Stevens2, Gita Tan-Sindhunata4, Masoud Zamani Esteki2, Christine de Die-Smulders2, Vivianne C.G. Tjan-Heijnen1, Lidewij Henneman4, erik sistermans4, Merryn Macville2 1Maastricht University Medical Center, Department of Medical Oncology, Maastricht, Netherlands; 2Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, Netherlands; 3Erasmus Medical Center, Department of Clinial Genetics, Rotterdam, Netherlands; 4Amsterdam UMC, Department of Human Genetics, Amsterdam, Netherlands; 5University Medical Center Groningen, Department of Clinical Genetics, Groningen, Netherlands; 6Radboud University Medical Center, Department of Human Genetics, Nijmegen, Netherlands; 7Leiden University Medical Center, Department of Clinical Genetics, Leiden, Netherlands; 8University Medical Center Utrecht, Department of Genetics, Utrecht, Netherlands Background/Objectives: Noninvasive prenatal testing (NIPT) for fetal aneuploidy screening using cell-free DNA derived from maternal plasma can incidentally raise suspicion for cancer. We detail malignancy suspicious–NIPT cases, describe clinical characteristics, chromosomal aberrations, and diagnostic routing of the patients with a confirmed malignancy. Methods: We retrospectively included patients with a malignancy suspicious-NIPT referred for tumor diagnostics between April 2017 and April 2020 from a Dutch nationwide NIPT implementation study, TRIDENT-2. NIPT profiles from patients with confirmed malignancies were reviewed, and the pattern of chromosomal aberrations related to tumor type was analyzed. We evaluated the diagnostic contribution of clinical and genetic examinations. Results: Malignancy suspicious–NIPT results were reported in 0.03% after genome-wide NIPT, and malignancies confirmed in 16 patients (16/48, 33.3%). Multiple chromosomal aberrations were seen in 23 of 48 patients with genome-wide NIPT, 16 patients (16/23, 69.6%) had a malignancy. Different tumor types and stages were diagnosed, predominantly hematologic malignancies. NIPT data showed recurrent gains and losses in primary mediastinal B-cell lymphomas and classic Hodgkin lymphomas. Magnetic resonance imaging and computed tomography were most informative in diagnosing the malignancy. Conclusion: In 231,896 pregnant women, a low percentage (0.02%) of NIPT results were assessed as indicative of a maternal malignancy. However, when multiple chromosomal aberrations were found, the risk of a confirmed malignancy was considerably high. Extensive oncologic examination may be guided by tumor-specific hallmarks in the NIPT profile and the clinical lessons learned from this study. References: Grants: The TRIDENT-2 study is supported by the Netherlands Organization for Health Research and Development (ZonMw, No. 543002001). Conflict of Interest: Catharina Heesterbeek: None declared, Sietse Aukema: None declared, Robert-Jan Galjaard: None declared, Elles Boon: None declared, Malgorzata Srebniak: None declared, Katelijne Bouman: None declared, Brigitte H.W. Faas: None declared, Lutgarde C.P. Govaerts: None declared, Mariette Hoffer: None declared, Nicolette Den Hollander: None declared, Klaske D. Lichtenbelt: None declared, Merel C. van Maarle: None declared, Lisanne van Prooyen Schuurman: None declared, Maartje C. van Rij: None declared, Heleen Schuring-Blom: None declared, Servi Stevens: None declared, Gita Tan-Sindhunata: None declared, Masoud Zamani Esteki: None declared, Christine de Die-Smulders: None declared, Vivianne C.G. Tjan-Heijnen Research funding: Roche (Inst), Eisai (Inst), Pfizer (Inst), Novartis (Inst), Lilly (Inst), Daiichi Sankyo/Astra Zeneca (Inst), Gilead Sciences (Inst), Honoraria: Novartis, Roche, Lilly, AstraZeneca, Pfizer, Lilly, Accord Healthcare, Novartis, Lidewij Henneman: None declared, erik sistermans: None declared, Merryn Macville Natl Institiute for Public Health & Environment (RIVM) - Center for Population Screening (CvB), Dutch NIPT Consortium, Netherlands Organization for Health Research and Development (ZonMW) (Inst) Uncompensated relationships: Illumina (Inst). C14.6 Machine learning-based detection of immune-mediated diseases from genome-wide cell-free DNA sequencing datasets Huiwen Che 1, Tatjana Jatsenko1, Lore Lannoo2, Kate Stanley1, Luc Dehaspe2, Leen Van Coillie2, Nathalie Brison2, Ilse Parijs2, Kris Van Den Bogaert1;2, Koenraad Devriendt1;2, Sabien Severi2, Ellen De Langhe2, Séverine Vermeire2, Bram Verstockt2, Kristel Van Calsteren2, Joris Vermeesch1;2 1KU Leuven, Department of Human Genetics, Leuven, Belgium; 2University Hospitals Leuven, Leuven, Belgium Background/Objectives: The early detection of tissue and organ damage associated with immune-mediated diseases (IMD), including autoimmune diseases (AID) and inflammatory bowel diseases (IBD), has been identified as key to improving long-term survival in the general population. In addition, AID are known risk factors for pregnancy. However, biomarkers to prospectively identify and stratify IMD patients are lacking. Methods: Here we developed a generic approach, coined GIPXplore that uses unsupervised clustering and supervised machine learning to investigate genome-wide signatures of cell-free DNA (cfDNA) profiles from both obstetric and general populations. IMD cases were identified from a population of 81,611 noninvasive prenatal screening (NIPS) profiles and a cohort of 161 non-pregnant individuals were evaluated. Results: We demonstrated that pregnant women with IMD have higher odds, 60-fold and 9-fold increase with lupus and IBD, respectively, of receiving inconclusive NIPS results. Unsupervised clustering of plasma cfDNA profiles showed similar disease-associated patterns in both pregnant and non-pregnant patients. A machine learning model incorporating such profile patterns detected 70% and 50% of patients with AID in these obstetric and general cohorts, respectively, at 95% specificity. Conclusion: Maternal IMD is a risk factor for inconclusive NIPS results. The ability to detect IMD patterns from the cfDNA profiles has the potential to stratify at risk pregnancies during routine NIPS and latent IMD in the general population. References: Grants: This study was supported by the Research Foundation-Flanders (FWO-Vlaanderen) (G080217N to JV) and FWO-SBO (S003422) to JV. Conflict of Interest: Huiwen Che: None declared, Tatjana Jatsenko Agentschap Innoveren en Ondernemen (VLAIO; Flanders Innovation & Entreprenership grant HBC.2018.2108), Lore Lannoo Clinical board for research and education Funding of the University Hospitals Leuven mandate funding., Kate Stanley EU H2020-MSCA-ITN-EJD-MATER (EU fund NUMBER 813707), Luc Dehaspe Patent application pending on 'Method for analyze cell-free nucleic acids'., Leen Van Coillie: None declared, Nathalie Brison: None declared, Ilse Parijs: None declared, Kris Van Den Bogaert: None declared, Koenraad Devriendt: None declared, Sabien Severi: None declared, Ellen De Langhe: None declared, Séverine Vermeire SV receive research grants from AbbVie, J&J, Galapagos, MSD, Pfizer, and Takeda., SV Receive speaker fees from AbbVie, Falk, Ferring, Hospira, MSD, Pfizer, Takeda, and Tillotts, Consultant for AbbVie, Avaxia, Celgene, Ferring, Galapagos, Genentech/Roche, Gilead, Robarts Clinical Trials, Hospira, Janssen, MSD, Mundipharma, Pfizer, Prodigest, Prometheus, Second Genome, Shire, and Takeda, Bram Verstockt BV is supported by Clinical Research Fund (KOOR) from the University Hospitals Leuven. BV is financially supported for research from Pfizer., Lecture fees from AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion., BV receives consultancy fees from Applied Strategic, Atheneum, Bristol Myers Squibb, Guidepoint, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, and Takeda., Kristel Van Calsteren University Hospitals Leuven advanced project funding (RT 1065)., Joris Vermeesch Research Foundation-Flanders (FWO-Vlaanderen) (G080217N to JV); EU H2020-MSCA-ITN-EJD-MATER (EU fund NUMBER 813707) to JV; FWO-SBO (S003422) to JV; KU Leuven funding (C14/18/092), Patent application pending on 'Method for analyze cell-free nucleic acids'.