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PURPOSESeveral groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.METHODSThe GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members.RESULTSBased on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%.CONCLUSIONTerminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

HIPBI-RD (Harmonising phenomics information for a better interoperability in the rare disease field) is a three-year project which started in 2016 funded via the E-Rare 3 ERA-NET program. This project builds on three resources largely adopted by the rare disease (RD) community: Orphanet, its ontology ORDO (the Orphanet Rare Disease Ontology), HPO (the Human Phenotype Ontology) as well as PhenoTips software for the capture and sharing of structured phenotypic data for RD patients. Our project is further supported by resources developed by the European Bioinformatics Institute and the Garvan Institute. HIPBI-RD aims to provide the community with an integrated, RD-specific bioinformatics ecosystem that will harmonise the way phenomics information is stored in databases and patient files worldwide, and thereby contribute to interoperability. This ecosystem will consist of a suite of tools and ontologies, optimized to work together, and made available through commonly used software repositories. The project workplan follows three main objectives: The HIPBI-RD ecosystem will contribute to the interpretation of variants identified through exome and full genome sequencing by harmonising the way phenotypic information is collected, thus improving diagnostics and delineation of RD. The ultimate goal of HIPBI-RD is to provide a resource that will contribute to bridging genome-scale biology and a disease-centered view on human pathobiology. Achievements in Year 1.

Rare diseases are those with a particularly low prevalence; in Europe, diseases are considered to be rare when they affect not more than 5 in 10000 persons in the European Union. The specificities of rare diseases make the area a veritable public health challenge: the limited number of patients and scarcity of knowledge and expertise single rare diseases out as a distinctive domain of high European added-value. The Orphan Medicinal Product Regulation of 1999 was the first European legislative text concerning rare diseases, followed by many initiatives, including recommendations by the Council of Ministers of the European Union in 2009. These initiatives contributed to the development of rare diseases policies at European and national level aimed at improving care for patients with rare diseases. A review of the political framework at European level and in European countries is provided to demonstrate how legislation has created a dynamic that is progressively improving care for patients with rare diseases. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".

International audience; The European Union Committee of Experts on Rare Diseases was entrusted with aiding the European Commission in a number of tasks, ranging from the monitoring of initiatives, to recommending improvements and actions to be pursued in the future, in addition to helping strengthen liaison at both European and International levels in the field of rare diseases. The three-year mandate of the EUCERD drew to a close in July 2013 with an impressive record. The EUCERD has laid down the foundations for future work so as to continue to advance in the key areas that have been identified as of interest for the rare disease community at large: centres of expertise, European Reference Networks, patient registries and databases, newborn screening, and indicators for national rare disease plans/strategies. The work of the Committee should now be continued by the newly formed European Commission Expert Group on Rare Diseases.

The development of centres of expertise (CE) and European Reference Networks (ERN) in the field of rare diseases (RD) is encouraged in the Council Recommendation on an Action in the Field of RD (2009/C 151/02) (8 June 2009) and most recently in the Directive on the application of patients’ rights in cross-border healthcare (2011/24/EU) (9 March 2011) as a means of organising care for thousands of heterogeneous RD affecting scattered patient populations across Europe. The European Union Committee of Experts on Rare Diseases (EUCERD http://www.eucerd.eu) issued a set of Recommendations on Quality Criteria for Centres of Expertise for Rare Diseases in Member States [1] to guide Member States (MS) in this area. The scope of CE in terms of disease coverage is an important issue as the expectation is to provide CE for all RD patients’ needs at national level. Denmark, France, Norway, Spain and the UK, for example, have already identified existing expertise at national level and/or established centres specialised in some RD/groups of RD which have proven to be very efficient in improving quality of care. The Scientific Secretariat of the EUCERD examined the current scope of CE in countries where they exist. CE were grouped by medical area. Three or more MS have designated centres for: juvenile arthritis/ paediatric rheumatological diseases, developmental anomalies and malformations/dysmorphology, hereditary cardiac diseases, dermatological diseases, epidermolysis bullosa, pituitary diseases or hypothalamic-hypophyseal diseases, lysosomal diseases, Prader-Willi syndrome, Fabry disease, mitochondrial diseases, haemophilia/ constitutional bleeding disorders, mastocytosis, hereditary diseases of the metabolism, porphyrias, epilepsies, neuromuscular diseases, amyotrophic lateral sclerosis, pulmonary diseases, severe pulmonary hypertension, cystic fibrosis, hereditary immune deficiencies, opthalmological diseases, genetic kidney disease, cranofacial anomalies, neurofibromatosis, Rendu-Osler disease. On the basis of this experience, a consensus can be thus identified that centres are required for around 12 groups of RD, 30 subgroups, and 26 individual diseases where centres currently exist in two or more countries. Most of these groups of RD fit into the traditional organisation of healthcare by medical area. However some grouping outside of traditional medical specialities is necessary, e.g. diseases of connective tissue, rare bone diseases, neurofibromatosis, multimalformation syndromes with intellectual disability, mitochondrial diseases, lysosomal diseases, any multi-systemic complex disease, etc. This analysis could be of use for MS currently considering the organisation of CE for RD. This work was carried out by the EUCERD Scientific Secretariat with the support of EC Joint Action N°20082291.

The 2009 Council Recommendation on an Action in the Field of Rare Diseases (2009/C 151/02) [1] encouraged Member States to elaborate a national plan or strategy for rare diseases before the end of 2013. One of the principal tasks of the European Union Committee of Experts on Rare Diseases (EUCERD) [2], through its Scientific Secretariat, was to analyse the results of the actions cited in the Recommendation, notably through the production of the annual report on the ‘State of the Art of Rare Disease Activities in Europe’ [3]. The 2014 edition of the report considers the impact of European policy and national plans/strategies (Figure ​(Figure1)1) on the organisation of health care and services for patients with rare diseases, including access to diagnosis and treatment, as well as considering progress in the field of registries, rare disease research initiatives, the genetic testing offer, access to information on rare diseases, patient organisations, and specialised social services. In terms of national plans and strategies for rare diseases, by end 2013, the deadline to elaborate national plans/strategies for rare diseases fixed by the Council Recommendation, most EU Member States had submitted a plan/strategy to their national authorities and sixteen countries have adopted a plan/strategy (Figure ​(Figure2).2). France and Spain have implemented and assessed their first plan. As their number one priority, most countries plan to identify and design centres of expertise for rare diseases. Many of these plans/strategies, however, have no dedicated budget for their actions, a result of the unfavourable economic context which may hinder the implementation of defined measures. The next challenge for EU Member States will be to effectively implement and assess these plans, which the new Commission Expert Group on Rare Diseases [4] will follow closely. Research in the field of rare diseases has been boosted in recent years due to European and international initiatives, such as European research projects funded via the DG Research and Innovation framework programmes and the E-Rare ERA-NET [5] as well as the creation of the International Rare Disease Research Consortium (IRDIRC) [6]. The Orphanet database [7] continues to expand and provides data collected in 37 European and surrounding countries with partner teams in Canada and Australia and negotiations ongoing in other world regions. Nearly all countries now have a national alliance for rare diseases ensuring that the voice of rare diseases, carried by Eurordis [8] at the European level, is heard. Figure 1 Emergence of concepts and initiatives surrounding rare diseases in Europe (December 2013) Figure 2 Stages of development of national plans or strategies for rare diseases in EU MS in December 2013