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      RD-Connect, NeurOmics and EURenOmics: collaborative European initiative for rare diseases

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          Abstract

          Although individually uncommon, rare diseases (RDs) collectively affect 6–8% of the population. The unmet need of the rare disease community was recognized by the European Commission which in 2012 funded three flagship projects, RD-Connect, NeurOmics, and EURenOmics, to help move the field forward with the ambition of advancing -omics research and data sharing at their core in line with the goals of IRDiRC (International Rare Disease Research Consortium). NeurOmics and EURenOmics generate -omics data and improve diagnosis and therapy in rare renal and neurological diseases, with RD-Connect developing an infrastructure to facilitate the sharing, systematic integration and analysis of these data. Here, we summarize the achievements of these three projects, their impact on the RD community and their vision for the future. We also report from the Joint Outreach Day organized by the three projects on the 3rd of May 2017 in Berlin. The workshop stimulated an open, multi-stakeholder discussion on the challenges of the rare diseases, and highlighted the cross-project cooperation and the common goal: the use of innovative genomic technologies in rare disease research.

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          Most cited references21

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          Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression

          Elevated blood pressure (BP) and chronic kidney disease (CKD) are complex traits representing major global health problems 1,2 . Multiple genome-wide association studies (GWAS) identified common variants giving independent susceptibility for CKD and hypertension in the promoter of the UMOD gene 3-9 , encoding uromodulin, the major protein secreted in the normal urine. Despite compelling genetic evidence, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants directly increase UMOD expression in vitro and in vivo. We modeled this effect in transgenic mice and showed that uromodulin overexpression leads to salt-sensitive hypertension and to age-dependent renal lesions that are similarly observed in elderly subjects homozygous for UMOD risk variants. We demonstrate that the link between uromodulin and hypertension is caused by activation of the renal sodium co-transporter NKCC2. This very mechanism is relevant in humans, as pharmacological inhibition of NKCC2 is more effective in lowering BP in hypertensive patients homozygous for UMOD risk variants. Our findings establish a link between the genetic susceptibility to hypertension and CKD, the control of uromodulin expression and its role in a salt-reabsorbing tubular segment of the kidney. These data point to uromodulin as a novel therapeutic target to lower BP and preserve renal function.
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            Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

            Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.
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              Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

              We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.
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                Author and article information

                Contributors
                Hanns.Lochmuller@gmail.com
                Franz.Schaefer@med.uni-heidelberg.de
                Olaf.Riess@med.uni-tuebingen.de
                Journal
                Eur J Hum Genet
                Eur. J. Hum. Genet
                European Journal of Human Genetics
                Springer International Publishing (Cham )
                1018-4813
                1476-5438
                27 February 2018
                27 February 2018
                June 2018
                : 26
                : 6
                : 778-785
                Affiliations
                [1 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, , Newcastle University, ; Newcastle upon Tyne, UK
                [2 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Neuropediatrics and Muscle Disorders, Medical Center–University of Freiburg, Faculty of Medicine, ; Freiburg, Germany
                [3 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Genetics, Center for Molecular Medicine, , University Medical Centre Utrecht, ; Utrecht, The Netherlands
                [4 ]ISNI 0000000089452978, GRID grid.10419.3d, Leiden University Medical Center, ; Leiden, The Netherlands
                [5 ]GRID grid.473715.3, Centro Nacional de Análisis Genómico, Center for Genomic Regulation, CNAG-CRG, , Barcelona Institute of Science and Technology, ; Barcelona, Spain
                [6 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Department of Medical Genetics and Applied Genomics, , University of Tübingen, ; Tübingen, Germany
                [7 ]CMAST bvba, Strategic Collaborations, Munich, Germany
                [8 ]CMAST bvba, Strategic Collaborations, Temse, Belgium
                [9 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Centre for Rare Diseases, , University of Tübingen, ; Tübingen, Germany
                [10 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Division of Pediatric Nephrology, , Heidelberg University Center for Pediatrics and Adolescent Medicine, ; Heidelberg, Germany
                Author information
                http://orcid.org/0000-0003-2324-8001
                http://orcid.org/0000-0001-6234-582X
                http://orcid.org/0000-0002-6889-0121
                http://orcid.org/0000-0003-1565-654X
                http://orcid.org/0000-0001-7219-632X
                http://orcid.org/0000-0003-3299-4321
                http://orcid.org/0000-0002-4833-8057
                Article
                115
                10.1038/s41431-018-0115-5
                5974013
                29487416
                4ed098c6-eb96-4221-9a2c-37e3e476cf90
                © European Society of Human Genetics 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 October 2017
                : 21 December 2017
                : 24 January 2018
                Categories
                Review Article
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                © European Society of Human Genetics 2018

                Genetics
                Genetics

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