May 2016  ●   Issue 19


Highlights of the past year


RD-Connect, NeurOmics and EURenOmics:
highlights of the year

RD-Connect, the global research and infrastructure resource for rare diseases, has just passed its three-year mark, and significant progress has been made during the past year.

RD-Connect's unique online genomics platform has improved in functionality and is now also available to external users. Its functionality has been adapted to the needs of rare disease researchers thanks to feedback from project partners NeurOmics and EURenOmics, who are already using the platform to identify causative variants in their sequenced patients. The platform has been presented at several international meetings including the recent meeting of the European Society of Human Genetics (ESHG) in Barcelona and the European Conference on Rare Diseases & Orphan Products (ECRD) in Edinburgh.

To facilitate the work of biobanks and patient registries, RD-Connect has developed two interoperable catalogues: the ID Cards system, which provides overview information about the numerous existing registries and biobanks in Europe, and a sample catalogue providing searchable access to records of individual biosamples. The system has already been tested by four biobanks. Both catalogues were presented at a hands-on workshop at the RD-Connect annual meeting in Barcelona.

RD-Connect partners have released new bioinformatics tools to annotate variants affecting the amino acid sequence (UMD Predictor), splicing (HSF) and regulatory regions (ALFA), as well as the VarAFT system for variant prioritisation and filtration. These tools are integrated into the RD‐Connect genomics platform. Other tools can be used to facilitate drug design, clinical trial feasibility and enrolment of patients with premature stop codons.

One of our recent achievements in the area of ethical, legal and social issues and patient involvement is the “IRDiRC Recommended” status awarded to the previously published International Charter of Principles for sharing bio‐specimens and data (2014, Eur. J. Hum. Genet.). RD-Connect has also obtained local ethics approval for the central platform data repository in Barcelona, which allows the platform to accept data and user registrations from other projects.

RD-Connect increased its collaborations with the Global Alliance for Genomics and Health as well as with several biomedical research infrastructures on the European Strategy Forum on Research Infrastructures (ESFRI) roadmap. The extensive interactions with various partners focus particularly on identifiers and data interoperability. RD-Connect is engaged in extensive discussions with participants in the EU public health sphere, such as the Commission Expert Group on Rare Diseases, the EXPAND project for health data interoperability, and European Reference Networks.
More information is available in the RD-Connect’s Third Periodic Activity Report.

The two major RD-Connect partner projects, NeurOmics and EURenOmics, also completed their third year of activity. At the end of 2015, each project submitted their annual progress reports to the European Commission emphasising their significant achievements and progress towards their research goals. Highlights for each project include:


• Thanks to the data sharing policy adopted by the project, the first batches of data (sequencing and clinical) are now being shared within the consortium. After the 12 months “hold period”, NeurOmics data is shared within the wider rare disease research community via controlled access to the RD-Connect database. Raw exome and genome data from the project’s sequencing provider deCODE is now routinely uploaded to the European Genome-phenome Archive for long-term storage, and reprocessed through a standard pipeline before it is made accessible for online analysis in the RD-Connect genomics platform.

• Clinical questionnaires have been developed for all 10 diseases studied in NeurOmics and the Human Phenotype Ontology (HPO) has been used to map the clinical features specified in the questionnaires to standardised terminology and make it computer-accessible. The standardised questionnaires have been used to create a phenotypic database at PhenoTips which went live in December 2013. So far more than 1000 NeurOmics patients have been entered and stored at PhenoTips.

• In order to improve trial capacity for therapeutic trials, the Care and Trial Site Registry was expanded and holds now 316 sites in 45 countries of which 50 sites are registered for neurodegenerative diseases. A ‘phenotype search facility’ has been implemented in the CTSR as well.

• Standard operating procedures have been developed for Huntington’s disease (HD), spinal muscular atrophy (SCA), fronto-temporal lobe dementia (FTLD) and hereditary spastic paraplegias (HSP) patient sampling for biomarker studies. All HD samples have been obtained and are being RNA sequenced, while SCA, HSP and FTLD samples from patients and presymptomatic individuals are being collected. For the validation of existing biomarkers for neuromuscular diseases, different approaches have been tested and sample collection is ongoing. Profiling methods for metabolites and lipids in plasma and cerebrospinal fluid based on UPLC-HRMS (ultra-high performance liquid chromatography coupled high resolution mass spectrometry) have been developed. This database now includes >2000 unique lipid signals from 6 families and 22 different classes.



• Several innovative methodologies including pioneering diagnostic and disease activity assays (e.g. an endothelial cell assay for therapeutic monitoring in complement diseases) have been developed and a unique kidney-focused bioinformatic analysis pipeline containing information from 32 transcriptomic and proteomic datasets is now functional.

• EURenOmics performed exome sequencing in 120 families, which resulted in the discovery of novel genes associated with SRNS (4 genes), tubulopathy (2 genes), complement disorders (3 genes), Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT, 1 gene), and 7 new genomic rearrangements in complement disorders. Numerous potential disease genes are undergoing functional characterization. Moreover, causative mutations in known genes were found in 8 SRNS, 5 tubulopathy, 10 complement disease and 3 CAKUT families.

• In parallel, targeted Next Generation Sequencing assays capturing all known genes within each disease group have been developed for glomerular (34 genes), tubular, (39 genes) and complement diseases (29 genes). After careful assay validation, panel screening is being performed on all archived samples and incident patients. So far, panel sequencing has been performed in over one thousand patients with SRNS, tubulopathy or Atypical hemolytic uremic syndrome (aHUS) and the disease causing mutations were identified in many of them. The tubulopathy kit has been submitted for use as the national reference Next Generation Sequencing diagnostic tool in the UK.


Highlights from the RD-Connect Annual Meeting in Barcelona, 2016

The last RD-Connect Annual Meeting, which took place in Barcelona in March this year, provided a great opportunity for discussion and information exchange between the project partners. Some of the most significant updates presented at the meeting include:

• The RD-Connect platform officially launched in 2015. It already includes the exomes and phenomes of over 500 donors and expects around 2000 individuals to be included by the end of the Summer 2016.

• Thanks to feedback from NeurOmics beta-testers, the platform has included new functionality for genetic variant discovery, including compound-heterozygosis, effect prediction metrics, population frequencies, genotype:phenotype queries and links to external resources, such as ExAC, HGMD and many more.

• To enable simple external queries to find out whether a particular variant is present or absent in the RD-Connect dataset, the platform has implemented the GA4GH Beacon API and has joined the Beacon Network, for more sophisticated queries enabling clinicians to assess similarity between cases and perform genotype or phenotype matching,

• RD-Connect is leading the work on version 2 of the the Application Programming Interface of the GA4GH/IRDiRC MatchMaker Exchange project together with Genesis and the MME core developer group.

• RD-Connect's Adherence Agreement and Code of Practice have been approved by the Parc de Salut Mar Ethical Committee (Barcelona, Spain), and the genomics platform has been registered in the Spanish Agency for Data Protection. It means it is now possible for additional projects to securely share their data with RD-Connect.

• A proof-of-concept for linking of patient registry and biobank data using semantic web technologies was achieved, and many software developments on the registry and biobank sides have also been achieved, including import and integration of Orphadata/ORDO into the ID-Card catalogue to allow autocompletion of Disease Name and Codes in the disease matrix and testing of automated population of ID Cards for PatientCrossroads registries through Application Programming Interface (API) connection of the systems.

• The disease matrix of Patientcrossroads pilot registries was updated through Application Programming Interfaces, and its first automated updates to ID-Card catalogue were tested.

• ID-Card and Sample Catalogue systems have been interconnected in order to avoid duplication of information.

• In collaboration with the RD-Connect annual meeting, EuroBioBank held its 13th Network Assembly in Barcelona, and approved the integration plan with RD-Connect.

• Patient Advisory Council members have been allocated responsibilities for overseeing within the RD-Connect work packages to improve two-way communication.

Presentations from the meeting are available on the RD-Connect website.


Next Cross-Project Annual Meeting will take place in Berlin in May 2017

The next RD-Connect Annual Meeting will be held in Berlin in the first week of May 2017 together with the NeurOmics and EURenOmics projects, which will hold their working meetings in parallel. The conference will include a special "Policy & Impact" session on Wednesday 3rd of May to showcase the successes of the projects. Key politicians, patients, pharma companies and other stakeholders will be invited to attend.

We are looking forward to seeing you in Berlin next year!


Project news



Communicating RD-Connect to patients and families

Patient engagement in RD Connect via the Patient Advisory Committee

The importance of patient representation in the governance of rare disease research projects and its benefit for the projects' success has been repeatedly demonstrated. For this reason, RD-Connect implemented a Patient Advisory Council (PAC) and a Patient and Ethics Council (PEC)  linked with its partner projects EURenOmics and NeurOmics. The goal of these councils is to actively inform project partners of issues important to patients and guarantee that a patient-centric approach is implemented throughout project activities.

As with much research on rare diseases, RD-Connect, EURenOmics and NeurOmics navigate new research territory and this requires close collaboration between all stakeholders. To support the collaboration of project partners, the Patient Advisory Council also serves as a platform for educating researchers on patient perspectives. Patient representatives provide input on scientific issues, provide insight into their day-to-day experience of living with rare diseases to researchers and ensure the expectations of the wider patient population are met.

Building momentum and spreading the word to the rare disease community

Through active involvement in the project, members of the Patient Advisory Council have had an opportunity to learn about the most recent research achievements. This not only enables them to work towards better integration of the needs, expectations and priorities of patients in rare disease research but also to convey the achievements of the project to the wider patient community. A new website section “For patients and families” will be launched in June and is intended to communicate the aims and achievements of RD Connect, EURenOmics and NeurOmics and highlight how this is relevant to patients and families affected by rare diseases. To facilitate understanding of the technical terms used within the research projects, the Patient Advisory Council has also developed a glossary including short definitions and explanations of these terms. Content including short articles, interviews with clinicians, scientists and patients involved in rare disease research will be progressively added on the communication platform. Through this new website section the Patient Advisory Council aims to make the wider patient community feel better connected with the RD-Connect project. 

~ Virginie Bros-Facer, EURORDIS – European Organisation for Rare Diseases


Two workshops on interoperability of data in rare disease registries

Rare disease registries are key instruments in rare disease research that allow the study of the natural history of diseases and help define cohorts of patients eligible for clinical trials.

In order to maximise their utility, registries should aim to be set up in an interoperable manner. Interoperable data formats allow data from each registry to be pooled with data from other registries and other clinical and omics data, which enhances the potential for scientific discoveries in their own research field as well as in other fields.

Today many rare disease registries are not fully interoperable. To enable them to make their data more accessible, an appropriate starting point is to map the data items they collect to relevant ontologies and make use of common data elements (CDEs). The creation of interoperable rare disease resources as the basis for a global infrastructure is being developed in collaboration with partners such as Elixir and BBMRI.

July workshop with providers of registry systems

New rare disease registries can (and must!) be set up in interoperable way. In the rare disease community there is much need for software platforms to simplify the creation of new rare disease registries. Within RD-Connect we have three dedicated platforms: Patientcrossroads, the Rare Disease Registry Framework and Osse MDR.

In order to define criteria for the building up of new “RD-Connect oriented” registries, we are organising a meeting with the partner platforms, which will be held on July 27-29 at the Istituto Superiore di Sanità in Rome. Partners from NCATS and ISCIII, the task leader on CDEs and ontologies, and by other partners working on databases and patient registries, will attend. 

The July meeting is aimed at establishing criteria and facilities to select more “disease specific” data elements (DSDEs) that should be added to the case report form and establishing the reference ontologies for DSDEs annotation. We also wish to identify software services that would make registries Findable, Accessible, Interoperable and Reusable (FAIR) in order to establish a global data infrastructure.

The meeting is thus aimed to advance the creation of an “RD-connect toolkit” for the creation of interoperable registries. It will require reflection on the characteristics that a registry should have to be integrated with other sources inside the RD-Connect platform.

September Bring Your Own Data Workshop

The RD-Connect BYOD (Bring Your Own Data) Workshop to Link Rare Disease Registries will be a hands-on experience, where attendees work with FAIR data experts to make their (sample) data FAIR and linked to other data that has been made FAIR before. The workshop will consist of preparatory webinars (one as a presentation at the Summer School), brief plenary introductions and practical working groups where participants see practically how to make their data FAIR and linkable, link it other linkable data and see how easy it becomes to answer difficult queries. 

If you would like to find out more about the meetings or wish to be involved please contact rd-connect.wp2@iss.it

~ Sabina Gainotti , Istituto Superiore di Sanità (ISS), Rome


First EuroBioBank back-to-back meeting with RD-Connect

EuroBioBank, the first rare disease biobank network in Europe founded in 2001 and an associated partner of RD-Connect, successfully held its 13th Network Assembly in conjunction with the 2016 RD-Connect Annual Meeting in Barcelona. At the end of 2015, EuroBioBank agreed to act as the de facto biobank network of RD-Connect. The Barcelona joint meeting was the first step in the integration process and an opportunity for members to align with recent activities.

Representatives from 14 members participated in the Assembly, and one new member application was approved during meeting, bringing the current network to 26 members from 11 countries. Dr Marina Mora was re-elected as the Scientific Coordinator, and the continued administrative coordination by Fondazione Telethon was approved.

The RD-Connect EuroBioBank partnership brings together valuable experience and resources for the RD community. Analyses presented during the Assembly showed that the number of biospecimens in the EuroBioBank Sample Catalogue had increased steadily in the past two years, as well as a broadening sample types. In the last release (Feb 2016 edition), 148,000 biospecimens are available for research. More than 950 rare diseases are currently presented. The partnership does not only signify the integration of EuroBioBank Sample Catalogue into RD-Connect, but a development of bilateral synergy via the firm implementation of streamlined workflows, sharing of established biobanking standard operating procedures and compliance to the latest Ethical, Legal and Social Issues (ELSI) principles developed and recommended by RD-Connect. The steps for integration were discussed and agreed during the Network Assembly with dedicated sessions on the legal framework of data sharing and technical aspects of the RD-Connect Sample Catalogue. The Assembly closed with a guest presentation by Mike Brudno on Ontologies for Biobanks.

Many of the EuroBioBank biobanks are registered in their respective national node within BBMRI-ERIC, and a close link is maintained at the network level in the context of RD-Connect with BBMRI-ERIC. This connection will facilitate sample data interoperability and promote synergy in other ongoing initiatives in biobanking. The integration of EuroBioBank with RD-Connect is expected to take place between 2016 and 2017.

~ Mary Wang, Fondazione Telethon, Milan


New staff for RD-Connect


New Science Communication and Impact Coordinator
at RD-Connect

From May 2016, the position of the RD-Connect Science Communication and Impact Coordinator has been taken up by Dorota Badowska. Dorota studied biotechnology (major) and psychology (minor) at the Warsaw University, Poland, where she was awarded a BSc in 2009. Next, she moved to Göttingen, Germany to study neuroscience at the Georg-August University and International Max Planck Research School. In 2014, she completed her PhD in neuroscience at the Max Planck Institute of Experimental Medicine in Göttingen, Germany. Her research focused on studying interaction of genetic and environmental risk factors for schizophrenia using mouse models.

Within RD-Connect, she has joined the Newcastle team and will be responsible for synthesising and maximising the outputs of the project and research findings.

Contact Dorota:


New Research Infrastructure Project Manager

Virginie Bros-Facer joined EURORDIS in 2015 as Research Infrastructure Project Manager. She manages EURORDIS's participation in projects (including RD-Connect) related to infrastructures and technologies facilitating rare disease research such as patient registries, biobanks, clinical bioinformatics and next generation sequencing as well as ethical issues surrounding preclinical research.

She completed her MSc and a PhD in Neuroscience at King's College London and also worked at the UCL Institute of Neurology on several research projects aiming to develop new therapeutic strategies for motor neuron disease and other neuromuscular disorders. Virginie worked for several British research funding organisations, including as Director of Medical Research for Sparks, a children's medical research charity based in London.

Contact Virginie:


Other news


CNAG receives ISO accreditation for Next Generation Sequencing

RD-Connect partner Centre Nacional d’Anàlisi Genòmico (CNAG), hosts of the central RD-Connect genomic platform, has received the UNE-EN ISO/IEC 17025:2005 accreditation for its DNA and RNA Next Generation Sequencing platform and DNA methylation analysis. The accreditation covers the entire process, including bioinformatic analyses such as alignment and variant calling. This internationally recognised accreditation reflects the strict quality management and technical competence at CNAG.

The focus on quality of the generated sequencing data is essential for advancement in the genomic research and is highly important for RD-Connect and its partners. “Since CNAG started its operation in 2010 one of the most important elements of the offering to our collaborators was the quality of the data”, says Dr Ivo Gut, the director of CNAG. “Both international standards we are now registered for are strategic tools that minimize errors, increase productivity and insure reaching the highest standards possible to be able to fulfil the expectations of our collaborators. This is also crucial for the implementation of precision medicine.”


Morris Swertz wins a VIDI grant from the Dutch Organization for Scientific Research

Dr. Morris Swertz, an RD-Connect partner at the University Medical Center Groningen (UMCG) in the Netherlands, received one of the 87 prestigious VIDI grants from the Dutch Organization for Scientific Research. In his work, Morris Swertz focuses on bio/medical IT infrastructure, biobanking and -omics data integration projects. The VIDI grant of up to  €800,000 was awarded for his project "Scalable ‘big data’ methods towards personalized genome diagnostics", focusing on improving diagnostics for patients with genetic diseases.

Even though new Next Generation Sequencing techniques allow measuring not one but all variants in a patient’s DNA in one sequencing experiment, data interpretation challenges mean that diagnostic rates still lag behind. Genetics labs, which previously tested only one gene at a time, are now overwhelmed by huge amounts of sequencing data. The project will develop patient-oriented techniques to obtain knowledge about deleterious mutations more quickly for 'personalized whole genome' diagnostics.


PhD student vacancy at the Department of Genetics, UMC Utrecht

The Department of Genetics at the UMC Utrecht searches for a PhD student to join the project on molecular mechanisms of structural kidney malformations. It involves whole genome sequencing in a large patient cohort, computational integration of the sequencing data with gene expression and epigenetics data, and modelling experiments to functionally characterize the identified variants, genes and pathways.

More information available here.


Postdoctoral position at the Institute Imagine in Paris

The laboratory of Matias Simons will admit a postdoc to generate a mouse mutant using CRISPR/Cas9 techniques in order to investigate mechanisms controlling endocytosis and autophagy and their role in genetic kidney diseases. The candidate should hold a PhD or MD and have experience in mouse breeding, handling and phenotyping. Hands-on experience with modern imaging technologies or lipid metabolism will be an asset.

More information available here.


Feedback from the EURenOmics Annual Meeting

In the last three years the EURenOmics consortium has been working intensively on high-throughput research on rare kidney diseases. At the 3rd annual meeting held in Paris from 11th to 13th around 100 participants shared novel results, heard a number of stimulating keynote lectures, and debated best ways to progress within the work packages. Overarching themes were the challenges in genomic research, such as the potentials and limitations of whole exome sequencing, as well as models and tools in rare disease and developmental research, such as stem cells and model organisms. With several updates on RD-Connect activities and the chance for hands-on training with the RD-Connect bioinformatics platform, many participants used to chance to really make the most of collaborative research efforts.

To date EURenOmics published over 150 scientific publications to date, one of which presented in the Publications section below.

~ Charlotte Gimpel, Universitätsklinikum Freiburg


Featured publications 


EURenOmics: ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS

Korkmaz E, et al., (2015)
J Am Soc Nephrol

Coenzyme Q10 related mitochondropathies are among the very few causes of steroid resistant nephrotic syndrome (SRNS) that are amenable to treatment. Clinicians and geneticists of the PodoNet consortium, an RD-Connect partner working on databases and patient registries, have now provided a description of the clinical course of children and adolescents with a novel, predominantly renal mitochondropathy. Loss of ADCK4 (AarF Domain Containing Kinase-4) leads to reduced cellular coenzyme Q10 levels. Podocytes (cells wrapping around capillaries in kidneys) are rich in ADCK4, but lack the related ACDK3 found in most other tissues, which explains the predominantly renal damage cause by ADCK4mutations.
The 26 reported patients show a relatively late but more rapid onset of loss of renal function compared to two other common forms of genetically determined SRNS. The most common extrarenal manifestations were neurological problems; however, these were much less pronounced than in other mitochondrial forms of SRNS. Encouragingly, oral treatment with Coenzyme Q10 significantly reduced proteinuria (presence of proteins in urine) in two patients treated at a very early stage. However, many patients had already lost large parts of their renal function by the time of diagnosis.

Awareness of the clinical phenotype (adolescent onset nephrotic syndrome with chronic kidney disease) and inclusion of ADCK4 in Next Generation Sequencing (NGS) panels for diagnostic screening will hopefully increase the number of patients who are identified early on and may benefit from timely treatment.


The Implicitome: A Resource for Rationalizing Gene-Disease Associations

Hettne KM et al., (2016)
Plos One

Prioritizing potential disease-associated candidate genes and genetic variants for validation and follow up studies continues to be a challenge in biomedical research. For this publication, Literature Wide Association Studies (LWAS) for 13,000 genes were performed using a literature mining workflow approach. LWAS contain information regarding gene-disease associations explicitly stated by authors, but importantly there are also valuable "implicit" associations that can be gleaned from the literature. In a series of case studies, they demonstrate the advantage of LWAS in readily providing access to the relevant biomedical knowledge of any particular gene-disease combination, thus moving away from black box approaches. Experts can interpret potential biological mechanisms from the biomedical knowledge provided. The authors provide the LWAS dataset as nanopublications in compliance with FAIR (Findable, Accessible, Interoperable and Reusable) Data Publishing recommendations and a software tool (knowledge.bio) to facilitate data integration, use and reuse. An integration of the gene-disease implicitome into the RD-Connect platform is currently underway.


Limb-girdle muscular dystrophies — international collaborations for translational research

Thompson R, Straub V (2016)
Nature Reviews Neurology

The limb-girdle muscular dystrophies (LGMD) are a group of diverse genetic neuromuscular conditions that usually affect the proximal muscles of the hip and shoulder girdles. The genetic defects causing over 30 LGMD subtypes are already known, and thanks to new sequencing technologies, such as whole-exome and whole-genome sequencing, the range of genes and phenotypes associated with the LGMDs is expanding. The advent of new user-friendly computational approaches to analyse these large datasets and standardise phenotypic data capture is helping clinicians to adapt to this new genomic medicine paradigm. However, no curative therapies for LGMD have been developed yet. To accelerate translation of basic research to the clinic, well-phenotyped and genetically characterized patient cohorts are essential, while natural history studies can help develop appropriate outcome measures and biomarkers. Sharing genomic data can significantly speed up that process and facilitate the development of therapies for patients. This review by RD-Connect and NeurOmics authors presents the international collaborations that tackle the issues of translational research on limb-girdle muscular dystrophies, as well as the outcomes of large-scale LGMD sequencing programmes.


The risk of re-identification versus the need to identify individuals in rare disease research

Hansson MG et al., (2016)
European Journal of Human Genetics

Ethics literature and policy makers have been increasingly raising the concern about the safety of coding or de-identification of biospecimens and personal data of research subjects. Unauthorized re-identification might result in privacy invasions and possible breaches of confidentiality. On the other hand, identifying individual patients is crucial for medical research. This is particularly important in the case of rare diseases, for which data have to be shared between multiple independent studies worldwide. The article discusses the needs and arguments concerning de-identification and re-identification of patients and research subjects and propose solutions to balance the different needs within a framework of using unique encrypted identifiers.


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