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.