December 2016  ●   Issue 25




European Commission approves 23 European Reference Networks

On 15th December the Board of Member States of ERNs voted to approve all 23 ERN proposals submitted under the first wave (the 24th proposal, submitted under the 2nd call, will be assessed early in 2017).

European Reference Networks are networks connecting expert centres in the field of rare diseases and specialised healthcare, organised across borders. This concept has been developing and maturing over the past five years and represents a major innovation in care for Europe’s 30 million rare disease patients: although pan-European structures exist in the research domain, this is the first such enterprise in the health sphere. The Networks will create governance structures for knowledge sharing and care coordination across the EU to improve access to diagnosis and treatment, as well as high-quality healthcare provision. ERNs have been organised around broad disease groups, to ensure that no patient with a rare disease is left ‘without a home’ under an ERN.

This is a major innovation for rare diseases in Europe, involving 370 hospitals and almost 1000 highly specialised units across 26 Countries (25 EU Member States + Norway).

The full list of approved ERN applications is available via the official European Commission webpage.


RD-Connect contributes to the special issue of Human Mutation on Next Generation Sequencing and Human Genetic Disease

The end of 2016 is celebrated by a special issue of Human Mutation dedicated to "Next Generation Sequencing and Human Genetic Disease". The RD-Connect partners are key contributors with four papers dedicated to:

• From Wet-Lab to Variations: Concordance and Speed of Bioinformatics Pipelines for Whole Genome and Whole Exome Sequencing (Laurie et al., CNAG)

• How to Identify Pathogenic Mutations among All Those Variations: Variant Annotation and Filtration in the Genome Sequencing Era (Salgado et al., AMU)

• Actionable Genes, Core Databases, and Locus-Specific Databases (Pinard et al., AMU)

• WES/WGS Reporting of Mutations from Cardiovascular “Actionable” Genes in Clinical Practice: A Key Role for UMD Knowledgebases in the Era of Big Databases (Pinard et al., AMU)

This issue covers a range of topics, from clinical applications to bioinformatics analysis and future technology developments. The clinical application of Next Generation Sequencing deals with the concept of choosing the right assay — the ever-confounding question of exome versus genome, clinical reporting, and what should be reported in the clinic — along with a critical eye to the ethical and social issues in using Next Generation Sequencing in the clinic. A special section has been included for bioinformatics analysis, which addresses the wet lab processes, actual detection of sequence variation and copy number variation, and approaches to identifying pathogenic variations. This special issue also focuses on the applications of Next Generation Sequencing in cancer and upcoming concepts in the clinic: epigenetics and noncoding RNA. Finally, it is important to look into the future and the newer technologies that are coming to the clinic, the impact of treatment, and how to handle the large amount of data generated by these methods.


Collaborating on big data to unravel disease processes

Patients with the same illness often receive the same treatment, even if the cause of the illness is different for each person. Six Dutch universities are combining forces to chart the different disease processes for a range of common conditions. This represents a new step towards ultimately being able to offer every patient more personalised treatment. The results of this study have been published in two articles in the authoritative scientific journal Nature Genetics.

New phase

The researchers were able to make their discoveries thanks to new techniques that make it possible to simultaneously measure the regulation and activity of all the genes of thousands of people, and to link these data to millions of genetic differences in their DNA. The combined analysis of these ‘big data’ made it possible to determine which molecular processes in the body become dysregulated for a range of different diseases, from prostate cancer to inflammatory bowel disease, before the individuals concerned actually become ill. “The emergence of ‘big data’, ever faster computers and new mathematical techniques means it’s now possible to conduct extremely large-scale studies and gain an understanding of many diseases at the same time,” explains Lude Franke (UMCG), head of the research team in Groningen. The researchers show how thousands of disease-related DNA differences disrupt the internal working of a cell and how their effect can be influenced by environmental factors. And all this was possible without the need for a single lab experiment.

Large-scale collaboration in the Netherlands

The success of this research is the result of the decision taken six years ago by biobanks throughout the Netherlands to share data and biomaterials. This decision meant it became possible to gather, store and analyse data from blood samples of a very large number of volunteers. The present study illustrates the tremendous value of large-scale collaboration in the field of medical research in the Netherlands. Bas Heijmans (LUMC), research leader in Leiden and initiator of the partnership: “The Netherlands is leading the field in sharing molecular data. This enables researchers to carry out the kind of large-scale studies that are needed to gain a better understanding of the causes of diseases. This result is only just the beginning: other researchers with a good scientific idea will be given access to this enormous bank of anonymised data once they have undergone a screening.”

Personalised approach

Mapping the various molecular causes for a disease is the first step towards a form of medical treatment that better matches the disease process of individual patients. To reach that ideal, however, we still have a long way to go. The large-scale molecular data that have been collected for this research are the cornerstone of even bigger partnerships. The third research leader, Peter-Bram ’t Hoen (LUMC), says: “Large quantities of data should eventually make it possible to give everyone personalised health advice, and to determine the best treatment for each individual patient.”

Leiden University Medical Center (LUMC), one of the RD-Connect partners, has published two scientific articles in Nature Genetics: "Disease variants alter transcription factor levels and methylation of their binding sites" and "Identification of context-dependent expression quantitative trait loci in whole blood". The research has been made possible thanks to the cooperation within the BBMRI biobank consortium (Biobanking and BioMolecular resources Research Infrastructure) of six long-running Dutch population studies carried out by the university medical centres in Groningen (LifeLines), Leiden (Leiden Longevity Study), Maastricht (CODAM Study), Rotterdam (Rotterdam Study), Utrecht (Netherlands Prospective ALS Study) and by the Vrije Universiteit (Netherlands Twin Register) plus the national centralised computational facility of SURFsara and the ErasmusMC Human Genomics Facility HuGE-F. The study links in with the Personalised Medicine route of the Dutch National Research Agenda.


Help ELIXIR create the tools adjusted to your needs!

Elixir Excelerate program addresses the infrastructure needs of the rare disease community. The aim is to help create and maintain sustainable ELIXIR resources in the long term. As part of this effort ELIXIR needs to determine the current usage and needs of the rare disease community.

We kindly ask you to complete the rare diseases data resources and tools survey.

Deadline: 10 January

Your response will help in prioritizing the most important bioinformatics tools, what needs to be improved, and will ultimately lead to better ELIXIR services adapted to the requirements of the community. If you are not able to answer these questions yourself, please forward it to an appropriate colleague.

Complete the survey here.


Featured publications


Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion

Vasli N, et al., (2016)

Congenital myopathies are a diverse group of neuromuscular diseases characterized by muscle weakness and decreased muscle tone in neonates and children. The genetic cause is still unknown in many patients, which makes genetic counselling impossible and is an obstacle for better understanding of the disease mechanisms. To identify novel genetic causes of congenital myopathies, the authors of this study have sequenced the DNA of three consanguineous families. In six affected patients, they found mutations of the mitogen-activated protein triple kinase ZAK, which lead to dramatic reduction of the ZAK mRNA and protein levels. The patients displayed slowly progressive muscle weakness and decreased vital capacities. Further analysis revealed other features, such as contractures and certain abnormalities in the muscle fibres. This study, funded by RD-Connect, points out the role of the mitogen-activated protein kinase (MAPK) signalling in congenital myopathies. These findings will therefore help improve the molecular diagnosis of these rare myopathies.

The Human Phenotype Ontology in 2017

Köhler S, et al., (2016)
Nucleic Acids Research

Deep phenotyping is a comprehensive clinical analysis of the phenotype (physical characteristics of a person) that focuses on individual anomalies displayed by the patient instead of on the overall diagnosis. Deep phenotyping of rare disease patients is crucial for RD-Connect to link computationally accessible clinical records with genomic data. The Human Phenotype Ontology (HPO) - one of the RD-Connect partner projects – makes that possible. The HPO project aims at creating standardized system of terms describing symptoms and anomalies that could be used by clinicians and researchers worldwide.

HPO includes three components: the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components allow for computational deep phenotyping, as well as precision medicine (formerly known as personalized medicine) and integration of clinical data into translational research.

The HPO has become as a standard for describing phenotype abnormalities by numerous groups, such as international rare disease organizations, patient registries, clinical laboratories, biomedical resources and clinical software tools. HPO has therefore a great potential to facilitate global data exchange and discoveries that would help understand the mechanisms or various diseases. To better represent specific disease areas, the HPO project has organized workshops together with RD-Connect, EURenOmics and NeurOmics.

This update article reviews how the HPO project has progressed in the last two years, and summarized its main achievements and improvements.

Generation of an iPSC line from a patient with tyrosine hydroxylase (TH) deficiency: TH-1 iPSC

Jung-Klawitter S, et al., (2016)
Stem Cell Research

Induced pluripotent stem cells (iPSCs) can convert into every other cell type in the body, such as neurons, heart, and liver cells and therefore, have a great potential in the field of regenerative medicine. In contrast to the embryonic stem cells, iPSCs do not require any controversial manipulations of early stage human embryos. As discovered 10 years ago, iPSCs can be obtained by genetic reprogramming of adult cells, such as patient’s skin cells. Cells generated from iPSCs are genetically identical to the patient and thus could be safely used for a transplant without the risk of immune rejection.

Apart from regenerative medicine, iPSCs are a useful tool for research. Scientists are able to generate cell types that could normally be only possible to obtain via a surgery or after patient’s death - such as neurons or heart cells - and analyse how patient’s genetic variants influence their structure and function.

In this study, the authors used fibroblasts (cell type obtained from a skin biopsy) of a male patient with the deficiency tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. The fibroblasts were next converted into an iPSCs cell line and thoroughly tested. This work, supported by RD-Connect, presents the first iPSCs model system, which can be used to study the influence of the patient’s TH genetic variants on human cells. The iPSCs carrying those genetic risk variants can thus help understand the mechanisms of this rare metabolic disease and provide a useful tool for drug testing.


 Christmas time


 As Christmas and the New Year are upon us, RD-Connect would like to wish all the partners and newsletter readers a happy and joyful Christmas break.

We would like to take this opportunity to thank all our partners for the hard work through the year and we wish all of you a good start of the year 2017 !!!


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