Received: 26 November 2021 Revised: 13 January 2022 Accepted: 13 January 2022 DOI: 10.1111/cge.14113 REVIEW CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative Juan Luque1 | Ingrid Mendes1 | Beatriz Go  mez1 | Beatriz Morte1 | Miguel Lo pez de Heredia1 | Enrique Herreras1 | Virginia Corrochano1 | Juan Bueren2,1 | Pía Gallano3,4,5,1 | Rafael Artuch6,1 | Cristina Fillat7,8,1 |  Luis A. Pérez-Jurado9,10,11,1 | Lluis Montoliu12,1 | Angel Carracedo13,14,1 | José M. Millán15,16,1 | Susan M. Webb17,18,1 | Francesc Palau19,20,21,22,1,25 | The 23,24,25,1 CIBERER Network | Pablo Lapunzina 1 Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain 2 gicas (CIEMAT), Instituto de Investigaciones Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnolo n Jiménez Díaz (IIS-FJD), Madrid, Spain Sanitarias Fundacio 3 Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 4 Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant Pau), Barcelona, Spain 5 Universitat Autònoma de Barcelona, Barcelona, Spain 6 Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain 7 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 8 Universitat de Barcelona, Barcelona, Spain 9 Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain 10 Genetics Service, Hospital del Mar, Barcelona, Spain 11 Hospital del Mar Research Institute (IMIM), Barcelona, Spain 12 Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain 13 Grupo de Medicina Xeno mica, Centro Singular de Investigacio n en Medicina Molecular y Enfermedades Cro  nicas (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain 14 n Pública Galega de Medicina Xeno Fundacio mica (SERGAS), IDIS, Santiago de Compostela, Spain 15 Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain 16  mica, Instituto Investigacio Biomedicina Molecular Celular y Geno n Sanitaria La Fe, Valencia, Spain 17 Hospital S Pau, Dept Medicine/Endocrinology, IIB-Sant Pau, Research Center for Pituitary Diseases, Barcelona, Spain 18 Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain 19 Department of Genetic and Molecular Medicine, Hospital Sant Joan de Deu, Barcelona, Spain 20 Laboratory of Neurogenetics and Molecular Medicine—IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain 21 Institute of Medicine & Dermatology, Hospital Clínic, Barcelona, Spain 22 Division of Pediatrics, University of Barcelona School of Medicine, Barcelona, Spain 23 INGEMM-Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Madrid, Spain 24 n Sanitaria Hospital La Paz (IdiPAZ), Madrid, Spain Instituto de Investigacio 25 ERN-ITHACA, Madrid, Spain The CIBERER Network group affiliations are mentioned in Appendix A. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd. Clinical Genetics. 2022;101:481–493. wileyonlinelibrary.com/journal/cge 481 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 482 LUQUE ET AL. Correspondence Pablo Lapunzina, INGEMM–Instituto de Abstract Genética Médica y Molecular. IdiPAZ–Instituto n Biomédica CIBER (Center for Biomedical Network Research; Centro de Investigacio de Investigacion Sanitaria del Hospital Universitario La Paz-Universidad Auto noma de En Red) is a public national consortium created in 2006 under the umbrella of the Madrid–CIBERER- Centro de Investigacio n Spanish National Institute of Health Carlos III (ISCIII). This innovative research Biomédica en Red de Enfermedades Raras, ISCIII, Madrid–Paseo de la Castellana structure comprises 11 different specific areas dedicated to the main public health 261-28046, Madrid, Spain. priorities in the National Health System. CIBERER, the thematic area of CIBER Email: pablo.lapunzina@salud.madrid.org and plapunzina@ciberer.es focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mis- Funding information Instituto de Salud Carlos III; Ministerio de sion is to be a center prioritizing and favoring collaboration and cooperation Ciencia e Innovacion between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low- prevalence diseases, in line with the International Rare Diseases Research Consor- tium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this arti- cle, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research. KEYWORDS genetics, new therapeutic approaches, novel genes, rare diseases, research network 1 | I N T RO DU CT I O N selected through a competitive process, contributing more than 6000 researchers and a core staff of 804 people (Table 1).2 CIBER is a In 2006, a public consortium known as “Center for Biomedical Net- national collaborative network consortium belonging to ISCIII, the n Biomédica En Red) was work Research” (CIBER, Centro de Investigacio national body that translates relevant biomedical research results to created under the umbrella of the Spanish National Institute of Health the NHS. CIBER's thematic areas are: Bioengineering, Biomaterials, Carlos III (ISCIII). This highly innovative research structure comprises and Nanomedicine (CIBERBBN), Diabetes and Metabolic Diseases 11 thematic areas dedicated to the main public health priorities of the (CIBERDEM), Physiopathology of Obesity and Nutrition (CIBEROBN), National Health System (NHS),1 one of them being devoted to Liver and Digestive Diseases (CIBEREHD), Respiratory Diseases research on rare diseases (CIBERER). (CIBERES), Epidemiology and Public Health (CIBERESP), Mental In this article, we review CIBERER's 15-year journey and summa- Health (CIBERSAM), Frailty and Healthy Aging (CIBERFES), Cardiovas- rize the most outstanding results obtained in terms of internationaliza- cular Diseases (CIBERCV), Cancer (CIBERONC), and Rare Diseases tion, scientific production, gene discovery, contributions toward the (CIBERER) (www.ciberisciii.es). discovery of new therapies and novel genes associated to diseases, CIBER is integrated by researchers from universities, research cooperation with patient associations and many other topics related centers, hospitals, health administrations and health services, in addi- to RD research. tion to an important research structure rooted in patient care. There are 104 institutions associated to the CIBER structure. The main aim of the CIBER is to promote collaborative research, favoring synergies 2 | C I BE R CO N S O R TI U M , from a multidisciplinary approach to science. CIBER relies on a team COLLABORATION, AND NETWORKING IN of expert managers allocated to different technical departments. BIOMEDICAL RESEARCH There are areas supporting the internationalization and project departments managing more than 150 research projects, 30 at The CIBER constitutes a relevant research consortium of excellence in European level and 5 in the American continent, besides many collab- the fields of Biomedicine and Health Sciences within the Spanish NHS orations among various research groups. The Technology Transfer and the Science and Technology Research System. CIBER is struc- Area oversees licensing agreements with industry and manages patent tured into 11 thematic areas and comprises 427 research groups portfolios; the Contracting and Purchasing Department manages most LUQUE ET AL. TABLE 1 Characteristics of the CIBER structure and distribution of the 11 thematic areas Number of Total number of Number of Mean number of Percentage of Percentage of CIBER research researchers publications publications per Publications publication Publications publication acronym CIBER name groups (2020) in 2020 in 2020 group (2020) in Q1 (2020) in Q1 in D1 (2020) in D1 BBN Bioengineering, biomaterials 45 558 739 16.4 558 76 211 29 and nanomedicine CV Cardiovascular diseases 40 499 757 18.9 441 58 157 21 DEM Diabetes and associated 31 250 362 11.7 269 74 100 28 metabolic diseases EHD Liver and digestive diseases 44 402 690 15.7 396 57 204 30 ER Rare diseases 57 561 727 12.8 454 62 196 27 ES Respiratory diseases 33 394 789 23.9 391 50 156 20 ESP Epidemiology and public 51 557 1367 26.8 764 56 347 25 health FES Frailty and healthy aging 20 145 249 12.5 153 61 51 20 OBN Physiopathology of obesity 33 451 747 22.6 454 61 114 15 and nutrition ONC Cancer 50 618 711 14.2 456 64 238 33 SAM Mental health 23 423 852 37.0 516 61 197 23 Totals Spanish national biomedical 427 4858 7990 18.7 4852 61 1971 25 (CIBER) network research (Centro de Investigacio  n Biomédica en Red) 483 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 484 LUQUE ET AL. service contracts; and the Institutional Relations Area manages the 4 | C I B E R E R : T H E CE N T E R F O R negotiation of agreements and scientific contracts, providing legal BIOM EDIC AL NE T WORK R ES EA RC H ON support to the Innovation Unit. Lastly, the Communication Area is RAR E D I SE ASE S dedicated to the dissemination of CIBER's results, both internally (newsletters), and externally. CIBERER, the thematic area of CIBER devoted to RDs (www.ciberer. es/en) was launched in 2006. At present, it is composed of 75 research groups (57 CIBERER groups plus 18 associated clinical groups) belong- 3 | C I B E R ' S R E S O U RC E S A N D ing to consolidated research structures from universities, health insti- I N F R A S T RU CT U R ES tutions, research centers and hospitals nationwide. CIBERER is organized into seven different research programs: (a) Translational CIBER has access to numerous infrastructures distributed nationwide. Genomic Medicine; (b) Inherited Mitochondrial and Metabolic Medi- CIBER is part of and contributes to the National Biobank Network cine; (c) Neurological Diseases; (d) Pediatric and Developmental Medi- through the CIBERER-Biobank, a public, non-profit biorepository cen- cine; (e) Sensorineural Pathology; (f) Endocrine Medicine; and tralizing the reception of RD biological samples; the CIBERES- (g) Hereditary Cancer, Hematological and Dermatological Diseases. Pulmonary Biobank Platform, which includes samples and matched The vision of CIBERER is to be a center where collaboration and clinical information from patients with lung diseases; and FATBANK, cooperation between biomedical and clinical research groups are priori- whose adipose tissue biobank constitutes a national referent. tized, with special emphasis on the aspects of genetic, molecular, bio- CIBERES-Pulmonary Biobank Platform has acted as the coordinator of chemical, and cellular research on RDs. This research is the basis for the National Biobank Network Platform until recently. providing new diagnostic and therapeutic tools, favoring the translation Other specialized centralized platforms are: (1) the so-called Sin- of research from the scientific environment of the laboratory to gular Scientific and Technical Infrastructures (ICTS), which are large healthcare settings. CIBERER is aligned with the new Horizon European installations, resources, facilities, and services, unique in its kind, Program and it shares the International Rare Diseases Research Consor- dedicated to cutting edge and high-quality research and technologi- tium (IRDiRC) vision and goals.3 IRDiRC is an initiative launched in 2010 cal development, as well as to promote exchange, transmission and by the European Commission and the National Health Institutes of the preservation of knowledge, technology transfer, and innovation. United States to achieve 1000 new therapies and innovative diagnostic CIBER coordinates NANBIOSIS, an important ICTS for the develop- tools, in addition to a global network of national registries, by 2027. ment of nanotechnology or biomaterials-based products from their The specific CIBERER's objectives are mainly based on the develop- design phase to their preclinical validation stage; (2) Bioinformatics ment of new treatments and the improvement in access to the diagnosis platforms: both CIBEREHD and CIBERER areas, have developed of RDs. In order to achieve this challenge, CIBERER maintains close collab- platforms performing data quality control services, gene expression oration with all the stakeholders involved in the RD field, both at a analysis, genomic mapping, variant analysis, and data mining; national and international level to (a) Establish and provide access to har- (3) BiblioPRO, a virtual library of documents in Spanish on health- monized and relevant RD data and information; (b) Carry out the molecu- related quality of life and health outcomes perceived by patients lar and clinical characterization of RD; (c) Promote translational, preclinical, (Patient Reported Outcomes-PRO); (4) Neuroimaging Platform, and clinical research (d) Rationalize ethical regulations and procedures. To a database containing thousands of neuroimages developed by cover all these aspects, the following lines of action were defined: net- CIBERSAM; (5) Patient registry platforms: the REHEVASC platform working, excellence research, collaborative and cooperative research, collects medical records from patients with rare liver diseases from translation, and transfer of results, as well as social visibility of RDs. In 17 hospitals nationwide and the National Chronic Hepatitis C Data- addition, the internationalization of research, the effective relationship base in collaboration with the Spanish Association for the Study of with the productive sector and the institutional visibility are continuously the Liver (AEEH); and the RENACER Patient Registry is a joint initia- being promoted to complement the aforementioned lines of action. tive of the CIBERCV and the Spanish Agency of Medicines and Med- ical Devices that, in collaboration with the Spanish Society of Cardiology and other medical societies, registers cardiovascular dis- 5 | CIB ER A ND CIB E RER' S SCI ENT I FIC ease patients. Additionally, CIBEREHD coordinates the Hepamet PRODUCTION cohort and the European NAFLD Registry (non-alcoholic fatty liver disease), and CIBERER takes part in the National Registry of patients The global scientific productivity of the CIBER Consortium in its 15 years with RDs, being the promoter of GenRaRe, a clinical registry of of existence has been very relevant, thus becoming one of the top genetic diseases. 10 national institutions according to its scientific production. As shown In addition to the aforementioned infrastructure, CIBER partici- by the relevant statistics, an indexed publication with a CIBER affiliation is pates in the ITEMAS Network, a platform promoted by the ISCIII displayed every 66 min in Medline; specifically  two publications/day supporting healthcare innovation. Its objective is to ensure that ideas have CIBERER affiliation (727 publications in 2020; Table 1 and Figure 1). of health professionals on innovation are delivered to health Regarding its participation in projects and leadership, currently, services. CIBERER has more than 30 active grants underway in the frame of 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LUQUE ET AL. 485 different national and international calls. Furthermore, CIBERER has worldwide in which CIBER Consortium and CIBERER play a very active financed 85 intramural projects in the past 10 years, for an overall role by leading the Spanish action. CIBERER groups are represented in amount of more than 4.5 million euros. Moreover, CIBERER has practically all the work programs of the Spanish “mirror group” of this recently received close to 8 million euros to deploy two projects initiative, (e) The RD-Connect project,9 which gave rise to the RD- focused on the genetic aspects of the COVID-19 pandemic and the Connect Community later on, was launched in November 2012 as a implementation of the IMPaCT project (see below). 6-year project funded by the European Commission. CIBERER partici- pated as an associated member of the consortium; (f) Genome- phenome Archive (EGA)10 is one of the two largest archives encourag- 6 | INTERNATIONAL PARTICIPATION OF ing the distribution and sharing of genomic and phenotypic data, C I BE R E R adopting strict protocols for information management, storage, security and dissemination such as those proposed by ELIXIR, an European plat- CIBERER researchers participate and are beneficiaries of relevant form coordinating, integrating and sustaining bioinformatics resources national and international projects within the scope of RDs. Some of across its member states where many CIBER groups participate very the initiatives in which CIBERER is engaged are: (a) Since 2010, actively; (g) Global Alliance for Genomics and Health (GA4GH)11 is an 4 CIBERER supports the coordination of Orphanet-Spain within international, non-profit alliance launched in 2013 that brings together Orphanet, the portal for RDs and orphan drugs that has become a con- more than 600 leading organizations working on the generation of sortium of 40 countries, within Europe and across the globe.5 CIBERER models and standards to enable the responsible, voluntary and secure is in charge of translation of Orphanet contents into Spanish, which is sharing of omics and health-related data. CIBERER is one of its mem- relevant for more than 470 million people in the world regarding medi- bers; (h) European Openscreen,12 an ERIC (European Research Infra- 5 cal, scientific and social aspects of RDs. This resource, along with structures Consortium) integrating high-throughput screening facilities MAPER, a database of available RD research resources in Spain, makes for molecules and drug development comprising more than 140 000 CIBERER an institution generating and giving access to the largest compounds and offering open access to resources for researchers from amount of information about RD related activities in Spain; academic institutions. (i) The European infrastructure EATRIS,13 the 6 (b) European Joint Program on Rare Diseases (EJPRD); this specific main support structure for translational biomedical research in biomedi- Joint Action for RD has brought together all those European institu- cine in Europe, is widely represented in the consortium, with 14 health tions working in this field with the aim of improving the integration, research institutions. Likewise, many of the CIBER's consorted institu- effectiveness, production and social impact of RD research. The EJPRD tions participate in SCReN, the Platform of Clinical Research and Clini- brings together more than 130 institutions from 35 countries to create cal Trial Units, which in turn is integrated into ECRIN,14 its equivalent a sustainable ecosystem enabling a virtuous cycle between research, at European level; (j) RD-CODE project14 promotes the use of the care and medical innovation; (c) The IRDiRC consortium7 is a global Orphanet nomenclature for implementation into health information effort to contribute to the development of new therapies and to accel- systems, thus enabling data sharing at European level in a standardized erate and facilitate RD diagnosis. CIBERER played an active role during and consistent manner. the genesis of the consortium, being involved in the bilateral meetings In 2020, The Council of Ministers of the Spanish Government held between the European Union (EU) and the National Institutes of approved “The Spanish Strategy for Personalized Medicine” with a total Health (NIH), and participating since then and up until recently in the funding of 77.3 million euros. The first action of the newly adopted consortium's interdisciplinary working group, in which CIBER members strategy, reflected in the Emergency Plan for Science and Innovation, continue performing different responsibilities; (d) The 1 + Million was the Call for the launch of the Infrastructure for Precision Medicine Genomes8 is one of the most ambitious initiatives in precision medicine associated with Science and Technology (Infraestructura de Medicina de F I G U R E 1 Number of CIBERER publications per year. The total number of original publications in the 2007–2020 period has been 7445 [Colour figure can be viewed at wileyonlinelibrary.com] 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 486 LUQUE ET AL. n Asociada a la Ciencia y Tecnología̧ IMPaCT). With an endow- Precisio TABLE 2 CIBERER representation in the European reference ment of 25.8 million euros, it will foster scientific knowledge and networks increase the capacity to exploit all the information available improving European reference CIBERER group– the quality and efficiency of the healthcare system. This initiative com- network (ERN) Acronym Institution prises three programs: Predictive Medicine, Data Science, and Genomic Rare neuromuscular EURO-NMD Hospital de la Santa Medicine, two of which are led by CIBER (Predictive Medicine and diseases Creu i Sant Pau Genomic Medicine; CIBERESP and CIBERER, respectively). Hospital Universitario La CIBERER also coordinates the ENoD initiative (Undiagnosed Rare Fe Diseases Program); this project has achieved a diagnosis for 29% of Hospital Sant Joan de Déu the patients eligible for the program, thus facilitating appropriate Hospital Universitario genetic counseling to many families. Vall d'Hebron Hereditary metabolic METAB-ERN Hospital Universitario disorders 12 de Octubre 7 | C I B E R E R P A R T I C I P A T I O N I N T HE Hospital Universitario EUROPEAN REFERENCE NETWORKS Santiago de Compostela European reference networks (ERNs)15 are virtual networks involving Hospital Universitario healthcare providers across Europe. They aim to tackle complex or de Cruces RDs and conditions that require highly specialized treatments and a Hospital Universitario concentration of knowledge and resources. There are 24 ERNs involv- Vall d'Hebron ing 25 EU countries plus Norway, with over 900 healthcare units Hospital Sant Joan de located in more than 300 hospitals and covering all major disease Déu groups. CIBERER groups participate in nine ERNs: EURO-NMD, Rare neurological ERN-RND Hospital Sant Joan de diseases Déu METAB-ERN, ERN-RND, Endo-ERN, ITHACA, BOND, TRANS- n Hospital Vall d'Hebro PLANTCHILD, ERN GUARD-HEART, and EuroBloodNet (Table 2). Hospital Universitario Clinic de Barcelona Rare hematological EuroBloodNet Hospital Universitario 8 | M A I N C O N TR I B U TI O N O F G E N ET I C diseases Vall d'Hebron RESEARC H BY CIB E RER Rare endocrine Endo-ERN Hospital Universitario conditions Vall d'Hebron In the past 15 years, CIBERER researchers have contributed to the Hospital Universitario discovery and description of new entities and/or associated genes. At de Cruces least 100 new genes associated with human disease have been Hospital de la Santa described by CIBERER groups in the last decade, in many cases Creu i Sant Pau (71) leading the publication as first or senior authors (Supplementary Rare congenital ITHACA Hospital Universitario La Table 1). Similarly, CIBERER researchers have described a number of malformations and Paz new disorders. The main contributions occurred in the fields of rare rare intellectual Hospital Sant Joan de disability Déu bone diseases, central and peripheral nervous system, metabolics, Hospital Universitario oncogenetics, or vision and hearing impairments, among others. Vall d'Hebron CIBERER's groups have contributed with the discovery of many Rare bone diseases BOND Hospital Universitario La new diseases and genes associated to previously known disorders. Paz For example, one of the many contribution was the finding in 2011 of Hospital Universitario a new gene (MAX) associated to hereditary pheochromocytoma (PCC) Virgen de la Arrixaca in 8 single patients.16 Transplantation in TRANSPLANT- Hospital Universitario La children CHILD Paz Rare and low- GUARD- Hospital Universitario prevalence complex HEART Virgen de la Arrixaca 9 | O R P H A N D R U G S , NE W T H E R A P I E S , diseases of heart A N D RE P U RP OSE D D RU GS C ON TR I B U TE D B Y C I BE R E R (FDA). CIBERER has sponsored 12 of the 25 orphan drugs. These In the past 10 years, CIBERER has contributed with the designation of drugs/compounds with an orphan designation are listed in Table 3. 25 orphan drugs by either the European Medicines Agency (EMA) or In addition, the different research programs developed by its American counterpart, the Federal Food and Drugs Administration CIBERER over the last decade have resulted in 28 patent applications 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LUQUE ET AL. 487 TABLE 3 Orphan drug designations with CIBERER as sponsor Substance Indication/RD Sponsor Agency Reference Lentiviral vector carrying the Fanconi anemia-A Fanconi anemia type A CIBER EMA EU/3/10/822 (FANCA) gene FDA FDA 16–5193 Lentiviral vector containing the human liver and Pyruvate kinase deficiency CIBER EMA EU/3/14/1330 erythroid pyruvate kinase (PKLR) gene FDA FDA 16–5168 Temsirolimus Adrenoleukodystrophy CIBER EMA EU/3/16/1669 Hematopoietic stem cells modified with a lentiviral Leukocyte adhesion deficiency type I CIBER EMA EU/3/16/1753 vector containing the CD18 gene FDA FDA 16–5453 Ubiquinol Primary coenzyme Q10 deficiency syndrome CIBER EMA EU/3/16/1765 Metformin Progressive myoclonic epilepsy type 2 (Lafora CIBER EMA EU/3/16/1803 disease) FDA FDA 17–6161 Etamsylate Hereditary haemorrhagic telangiectasia CSIC & EMA EU/3/18/2087 CIBER Gefitinib Fanconi anemia CIBER EMA EU/3/18/2075 Afatinib Fanconi anemia CIBER EMA EU/3/18/2110 Dimethyl fumarate Adrenoleukodystrophy CIBER EMA EU/3/19/2236 Autologous skin equivalent graft composed of Epidermolysis bullosa CIBER EMA EU/3/20/2253 keratinocytes and fibroblasts genetically corrected by CRISPR/Cas9-mediated excision of mutation- carrying COL7A1 exon 80 L-Ergothioneine Cystinuria CIBER EMA EU/3/21/2445 with a therapeutic potential. Seven of them have been licensed, prevalence disease in Spain. At present, FEDER has more than signing long-term cooperation agreements with leading companies in 370 affiliated associations and has developed a network of strategic the pharmaceutical and the biotech sectors. These technologies are alliances and collaborations with EURORDIS (a non-governmental being developed to treat different groups of RD including patient-driven alliance of patient organizations representing 949 RD mitochondrial,17 metabolic,18 skin,19 or rare hematological diseases.20 patient organizations in 73 countries.), RDI (Rare Disease Interna- Thus, it is worth highlighting our ex-vivo lentiviral vectors-based gene tional, the global alliance of people living with a RD of all nationalities therapy programs. These are our most advanced programs in clinical across all RDs), SWAN (Syndromes Without A Name) and ALIBER phases, three of which are licensed and running in collaboration with (Ibero-American Alliance for RDs). Rocket Pharmaceuticals, Inc. Specifically, they are focused on pyruvate In 2017, CIBERER constituted the Patient Advisory Council (PAC) kinase deficiency (PKD),21 leukocyte adhesion deficiency type I (LAD- with the aim of fostering patients' participation in CIBERER's activities 1)22 and Fanconi Anemia (FA), the latest being the most advanced one, as a means to know first-hand their expectations and needs and to 23 running under a globally registered clinical trial. In 2019 CIBERER has achieve their engagement in CIBERER's research policies. The PAC is reported a successful engraftment of gene-corrected hematopoietic integrated by various patient associations, nominated from the differ- stem cells in non-conditioned patients with FA, a DNA repair syndrome ent CIBERER research programs and renewed every 2 years. generated by mutations in any of the 22 FA genes discovered to date. CIBERER and FEDER have signed collaboration agreements The authors demonstrated that lentiviral-mediated hematopoietic gene focused on FEDER's participation in both the Scientific Advisory therapy reproducibly confers engraftment and proliferation advantages Board (SAB) and the PAC with two designated members, and on of gene-corrected hematopoietic stem cells supporting that gene ther- CIBERER's participation as advisor at the Information and Guidance apy should constitute an innovative low-toxicity therapeutic option for n y Orientacio Service for patients (Servicio de Informacio n; SIO) 24 this life-threatening disorder. launched and managed by FEDER. Additionally, most Principal Investi- gators of CIBERER's research groups are involved with patient associ- ations, serving as Scientific Advisors or as members of their Scientific 1 0 | A H A N D - I N - H A N D CO L L A B O R A T I O N Committees. W I T H P A T I E N T S A S S O C I A T I ON S CIBERER maintains extensive collaborations with patient associations 11 | T H E S PECIALTY OF GENETI CS OR representing all RDs. Noteworthy is the close collaboration with M ED I C A L GE N E T I C S I N SP A I N n Española de Enfermedades Raras; Spanish Alliance FEDER (Federacio of Rare Diseases), an umbrella organization established in 1999 with Spain is the only country in Europe that does not currently have this the aim of being the voice of  three million people living with a low- specialty. It is essential that the specialty of Clinical Genetics is 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 488 LUQUE ET AL. approved in Spain to facilitate the training of specialists in the diag- DATA AVAILABILITY STAT EMEN T nosis, management and treatment of genetic diseases. The lack of Data sharing is not applicable to this article as no new data were cre- regulation of the specialty causes a great heterogeneity in the type ated or analyzed in this study. of genetic services provided in the Hospitals with a serious inequity of patient access in the NHS. This situation delays diagnoses and OR CID their corresponding treatments in patients, hinders the prevention José M. Millán https://orcid.org/0000-0002-7211-9129 of new cases in families, reduces the efficiency of the health system (by requesting unnecessary or irrelevant tests) and does not guaran- RE FE RE NCE S tee that all professionals who provide genetic services are ade- 1. Pàmpols T, Ramos FJ, Lapunzina P, Gozalo-Salellas I, Pérez-Jurado LA, quately trained for this activity, which is detrimental to the health Pujol A. A view on clinical genetics and genomics in Spain: of chal- lenges and opportunities. Mol Genet Genomic Med. 2016;4(4):376- of citizens and the quality of life of patients. CIBERER as many 391. doi:10.1002/mgg3.232 other stakeholders have been reporting this irregular situation for 2. CIBER Activity Annual Report .; 2020. https://www.ciberisciii.es/ years. Memorias/2019/ENG/mobile/index.html#p=1 3. IRDiRC vision and goals. 2021. https://irdirc.org/about-us/vision- goals/ 4. Punto de acceso al sitio web de Orphanet-España. 2021. http:// 12 | FINAL REMARKS www.orphanet-espana.es/national/ES-ES/index/inicio/ 5. 2019 Activity Report, Orphanet Report Series, Report Collection; 2020. Although Spain has excellent standards in Public Health Services, https://www.orpha.net/orphacom/cahiers/docs/GB/ ActivityReport2019.pdf comparable to those of the most advanced economies in the world, 6. Project structure. 2021. https://www.ejprarediseases.org/what-is- there are still some hurdles preventing timely diagnosis and treatment ejprd/project-structure/ of RDs patients and a full deployment of Genomic Medicine in the 7. Cutillo CM, Austin CP, Groft SC. A global approach to rare diseases country. Some of these barriers are: (a) the lack of an official Clinical research and orphan products development: the international rare Genetics specialty;( b) the inequality in access to public and universal diseases research consortium (IRDiRC). 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Lentiviral-mediated gene therapy for pediatric patients with fanconi 100,7,1 89,1 anemia subtype A. 2021. https://clinicaltrials.gov/ct2/show/ Dalmau ; Sergio de Cima ; Susana de la Luna101,102,1; Noemí NCT04069533 De Luna103,1; Alfonso de Oyarzabal Sanz104,1; Miguel del 24. Río P, Navarro S, Wang W, et al. Successful engraftment of gene- Campo105,106,1; Ignacio del Castillo107,1; Lucía Del Pino Molina108,24,1; corrected hematopoietic stem cells in non-conditioned patients with  Angela Del Pozo1,23,24; Marcela del Río109,73,74,1; Aitor Delmiro58,36,1; Fanconi anemia. Nat Med. 2019;25(9):1396-1401. doi: Lourdes R. 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How to cite this article: Luque J, Mendes I, Go Gallano1,35; Eduard Gallardo103,1; Marta García113,73,74,1; Elena CIBERER: Spanish national network for research on rare García-Arumí66,1; María García-Bravo1,2; Angels García-Cazorla116,1; diseases: A highly productive collaborative initiative. Clinical Inés García-Consuegra36,1; Francesc Josep Garcia-Garcia69,7,1; Gema Genetics. 2022;101(5-6):481-493. doi:10.1111/cge.14113 García-García119,1; José Luis García-Giménez120,121,1; María Adelaida Garcia-Gimeno122,1; Sixto García-Miñaur1,23,24; Alberto García- 114,1 Redondo ; M. Teresa García-Silva123,36,1; Judit García- Villoria124,7,1; Fe García Santiago1,23,24; Gloria Garrabou69,7,1; Gema APPENDIX A Garrido1,12; Nuria Garrido-Pérez55,56,57,1; Sonia Gaztambide81,84,82,1; Mercedes Gil-Campos125,126 127,1; Judith Giroud-Gerbetant54,1; The CIBERER network Guillermo Glover 50,51,1  mez ; Paulino Go ; Beatriz Go mez-Puertas63,1; 1 Carmen Aguado1,26; Cristina Aguado27,1; Paula Aguilera149,7,1;Vir- Pilar Gonzalez-Cabo120,121,1; Ingrid Gonzalez-Casacuberta69,7,1; María 28,1 1,35 29,1 ginia Albiñana ; Laura Alías ; Berta Almoguera ; Javier González-del Pozo34,1; Lidia González-Quereda1,35; Adrián Alonso 30,1  nica Alonso-Ferreira ; Vero 31,1 ; María Isabel Alvarez- González-Quintana 58,36,1 ; Laura Gort124,7,1; Nadine Gougeard89,1; Mora32,7,1; Guillermo Antiñolo34,1; María L. Arbones35,1; Joaquín Eduard Gratacos98,8,7,1; Josep María Grau69,7,1; Daniel Arenas36,1; Emi Arjona28,1; Thais Armangue37,38,39,1; Judith Arm- Grinberg47,48,49,1; Guillermo Güenechea1,2; Rosa Guerrero70,24,1; strong40,1; María Arnedo41,1; Rafael Artuch1,6; Anna Aulinas Encarna Guillén-Navarro50,128,51,1; Mariona Guitart-Mampel69,7,1;  Maso 17,42,1 ; Almudena Avila-Fernandez 29,1 ; Carmen Ayuso 29,1 ; Isabel Armand Gutiérrez-Arumí129,1; Karen Heath1,23,24,163; Miguel Here- Badell 43,5,1 ; Celia Badenas 32,44,1 ; María L. Baeza 45,46,1 ; Montserrat  n Hernández-Chico107,1; Enrique Herreras1; Janet dia89,1; Concepcio Baiget1,3; Susanna Balcells47,48,49,1; María Juliana Ballesta- Hoenicka1,20; Aïda Homs1,9; Juan Andrés Jimenez-Estrada70,1; Cecilia 50,51,52,1 53,1 1,14 Martínez ; María-José Barahona ; Francisco Barros ; Jimenez-Mallebrera130,1; Cristina Jou131,1; Diana Luz Juarez- 54,1 55,56,57,1 69,7,1 23,24,25,1 Paola Chiara Bartoccioni ; M. Pilar Bayona-Bafaluy ; Sara Flores ; Pablo Lapunzina ; Fernando Larcher73,113,74,1; Benito Sanz1,23,24; Carmelo Bernabéu28,1; Sara Bernal1,35; Fiona Adriana Lasa1,35; Luis Lassaletta132,24,1; Ana Latorre-Pellicer133,1; Blanco-Kelly29,1; Alberto Blázquez58,36,1; Susanna Bodoy54,59,1; Mas- Daniel Linares1,7; José Luis Llacer89,1; Sara Llames134,135,74,1; Ester simo Bogliolo 60,61,1 ; Cristina Borralleras 62,1 ; Salud Borrego 34,1 ; Luisa  pez-Laso136,126 127,1; Alberto Lo Lopez-Gallardo55,56,1; Eduardo Lo pez- M. Botella 28,1 ; Francesc Bou de Pieri 1,9 ; Paola Bovolenta 63,1 ; Nereida  pez-Sánchez1,9; Miguel Lera1,24; Daniel Lopez-Lopez71,72,1; Marcos Lo Bravo-Gil 34,1 ; Alejandro Brea 1,14 ; Gloria Bueno-Lozano 64,1 ; Juan pez de Heredia1; Eduardo Lo Lo  pez Granados108,24,1; Isabel Lorda- Bueren1,2; Ana Bustamante29,1; Teresa Caballero65,24,1; Carlos Sanchez29,1; María Luisa Lozano94,51,1; Juan Luque1; Irene 63,1 66,1 32,7,1 149,7,1 70,24,1 Camacho-Macorra ; Yolanda Cámara ; Núria Camats- Madrigal ; Josep Malvehy ; Cristina Manguán García ;  Tarruella67,1; Angel Campos Barros1,23,24; Victoria Campuzano68,1; Elena Mansilla1,23,24; Clara Marco-Marín89,1; Gemma Mar-  69,7,1; José Antonio Caparro Lara Cantarero1,20; Judith Canto  s- fany137,48,49,1; Alberto Marina89,1; n Ramo Martí66,1; Salvador 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 490 LUQUE ET AL. Martí1,26; Yolanda Martin107,1; Miguel A. Martín58,36,1; Elena Martín- Tiebas29,1; Cristina Ugalde36,1; Olatz Ugarteburu124,7,1; Roser Hernandez.123,36,1; Inmaculada Martin-Merida29,1; Rosa Urreizti75,1; Inés Urrutia83,84,82,81,1; María Valencia70,1; Patricia Martínez83,84,82,81,1; Francisco Martínez-Azorín36,1; Beatriz Martinez- Vallcorba1,23,24; Elena Vallespín1,23,24; Isabel Varela-Nieto70,24,1; Ana 138,1 47,48,49,1 Delgado ; Núria Martínez-Gil ; Víctor M. Martínez- Vega1,14; Valentina Vélez-Santamaria76,77,1; Juan J. Vílchez160,1; Olaya 23,24,25,1 139,1 Glez ; M.A. Martínez-Momblán ; María Carmen Martínez- Villa158,1; Manuela Villamar107,1; Susan M. Webb1,17,18; José Manuel Romero50,51,52,1; Pilar Martínez Fernández1,23,24; Lucía Martínez Zubeldia45,46,1; Olga Zurita29,1. 113,73,74,1 40,1 55,56,57,1 1 Santamaría ; Loreto Martorell ; Patricia Meade ; , Centre for Biomedical Network Research on Rare Diseases  Alvaro  Meana134,135,74,1; Miguel Angel Medina140,141,1; Andrés (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Medrano1; Ingrid Mendes1; Cristina Méndez-Vidal34,1; José 2 , Hematopoietic Innovative Therapies Division, Centro de  n60,3,61,1; Serena M. Millán1,15,16; Pablo Minguez29,1; Jordi Minguillo Investigaciones Energéticas, Medioambientales y gicas Tecnolo Mirra 137,48,49,1 ; Belén Molla 89,1  ; Eduardo Molto 12,142,1 ; Raquel  n Jiménez (CIEMAT), Instituto de Investigaciones Sanitarias Fundacio Montero75,1; Lluis Montoliu1,12; Julio Montoya55,56,1; María Díaz (IIS-FJD), Madrid, Spain. Morán36,1; Constanza Moren69,7,1; Mireia Moreno89,1; José Carlos 3 , Genetics Department, Hospital de la Santa Creu i Sant Pau, Bar- Moreno1,23,24; Antonio Moreno-Galdo   67,1; Miguel Angel Moreno- celona, Spain. Pelayo107,1; María A Mori1,23,24; Matías Morin107,1; Beatriz Morte1; 4 , Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB 51,143,1 124,7,1 Victoriano Mulero ; Gerard Muñoz-Pujol ; Rodolfo Sant Pau), Barcelona, Spain. Murillas73,74,1; Silvia Murillo-Cuesta70,24,1; Andrés Nascimento130,1; 5 , Universitat Autònoma de Barcelona, Barcelona, Spain. Susana Navarro1,2; Plácido Navas96,1; Julián Nevado23,24,25,1; Adrià 6 , Clinical Biochemistry Department, Institut de Recerca Sant Joan  Nicolas54,1; M. Angela Nieto144,1; Mar O0 Callaghan116,1; Leticia de Déu, Barcelona, Spain. Olavarrieta107,1; Aida Ormazabal75,1; Paula Ortiz-Romero1,9; Ana 7 , Institut d'Investigacions Biomèdiques August Pi i Sunyer 145,1 146,1 54,117,1 Osorio ; David Páez ; Manuel Palacín ; M. Gabriela (IDIBAPS), Barcelona, Spain. Palacios-Verdú147,1; Francesc Palau1,1922; Adrián Palencia- 8 , Universitat de Barcelona, Barcelona, Spain. Campos 70,1  ; Federico V. Pallardo 120,121,1 ; María Palomares 1,23,24 ; 9 , Department of Experimental and Health Sciences, Universitat María Peña-Chilet71,72,1; Belén Pérez110,24,1; Javier Perez- Pompeu Fabra (UPF), Barcelona, Spain. Florido71,72,1; Débora Pérez-García148,1; Eva Perez-Jimenez89,1; Luis 10 , Genetics Service, Hospital del Mar, Barcelona, Spain. A. Pérez-Jurado1,911; James R. Perkins140,141,1; Rosario Perona70,24,1; 11 , Hospital del Mar Research Institute (IMIM), Barcelona, Spain. Juan Pie 133,1 s ; Tomàs Pino 66,1 ; Sheila Pinto 28,1 ; Miriam Potrony 32,7,1 ; 12 , Department of Molecular and Cellular Biology, National Cen- Susana Puig149,7,1; Joan n Anto Puig-Butille150,33,7,1; Beatriz tre for Biotechnology (CNB-CSIC), Madrid, Spain. Puisac133,1; Roser Pujol60,3,1; Aurora Pujol76,102,1; Óscar Quintana1,2; 13  mica, Centro Singular de Investigacio , Grupo de Medicina Xeno n Raquel Rabionet47,48,49,1; María José Ramírez de Haro60,3,1; Feliciano nicas (CIMUS), Universidade en Medicina Molecular y Enfermedades Cro  n152,1; J. Ramos151,133,1; Juan A.G. Ranea140,141,1; Judith Reina-Castillo de Santiago de Compostela, Santiago de Compostela, Spain. Eugenia Resmini1,5,17; Antonia Ribes124,7,1; Itxaso Rica81,83,84,1; Eva 14  n Pública Galega de Medicina Xeno , Fundacio  mica (SERGAS), 110,63,24,1 153,1 1,2 Richard ; Pau Riera ; Paula Río ; Rosa Riveiro- IDIS, Santiago de Compostela, Spain. Alvarez29,1; José Rivera94,51,1; Ana Rivera-Barahona70,1; Mercedes 15 , Unidad de Genética, Hospital Universitario y Politécnico La Fe, 78,1 95,1 Robledo ; Juan Carlos Rodriguez-Aguilera ; Lourdes Rodríguez- Valencia, Spain. de la Rosa70,24,1; Agustí Rodríguez-Palmero76,154,1; Pilar Rodriguez- 16  mica, Instituto Investiga- , Biomedicina Molecular Celular y Geno Pombo 110,63,24,1 ; Laia Rodriguez-Revenga 32,7,1 ; Benjamín Rodríguez- n Sanitaria La Fe, Valencia, Spain. cio Santiago1,3; Víctor Rodríguez-Sureda155,156,1; Marta Rodríguez de 17 , Hospital S Pau, Dept Medicine/Endocrinology, IIB-Sant Pau, 29,1 28,1 Alba ; Santiago Rodríguez de Cordoba ; Carlos Romá- Research Center for Pituitary Diseases, Barcelona, Spain.  Mateo120,121,1; Vicente Rubio89,1; Angela Ruiz28,1; Montserrat 18 , Departamento de Medicina, Universitat Autònoma de Barce- 76,1 1,9 70,23,1 Ruiz ; Carlos Ruiz-Arenas ; Victor Luis Ruiz-Perez ; Eduardo lona, Barcelona, Spain. Ruiz-Pesini55,56,1; Clara Ruiz-Ponte1,14; Josep Rullo54,1; Lidia 19 , Department of Genetic and Molecular Medicine, Hospital Sant 100,7,1 146,1 157,1 Sabater ; Juliana Salazar ; Eduardo Salido ; Carolina Joan de Deu, Barcelona, Spain. Sanchez-Jimeno29,1; Ana María Sánchez Cuesta96,1; María José 20 , Laboratory of Neurogenetics and Molecular Medicine - IPER, 50,51,1 63,1 1,14 Sánchez Soler ; Fulvio Santacatterina ; Marta Santamarina ; Institut de Recerca Sant Joan de Déu, Barcelona, Spain. Alicia Santos1,17; Carlos Santos-Ocaña96,1; Fernando Santos 21 , Institute of Medicine & Dermatology, Hospital Clínic, Barce- 1,23,24 89,1 70,24,1 Simarro ; Pascual Sanz ; Leandro Sastre ; Agatha lona, Spain. Schlüter76,1; José Carlos Segovia1,2; María Segura-Puimedon158,1; 22 , Division of Pediatrics, University of Barcelona School of Medi- 140,141,1 1,35 116,1 Pedro Seoane ; Clara Serra-Juhe ; Mercedes Serrano ; cine, Barcelona, Spain. José M. Serratosa159,1; Teresa Sevilla160,161,1; Jordi Surrallés60,3,61,1; 23 , INGEMM-Instituto de Genética Médica y Molecular,Hospital 29,1 149,7,1 Saoud Tahsin-Swafiri ; Gemma Tell-Martí ; Jair Antonio Universitario La Paz, Madrid, Spain. Tenorio-Castaño23,24,25,1; Eduardo Tizzano91,67,1; Ester Tobias69,7,1; 24  n Sanitaria Hospital La Paz (IdiPAZ), , Instituto de Investigacio 124,7,1 162,1 Frederic Tort ; Laura Trujillano ; María José Trujillo- Madrid, Spain. 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LUQUE ET AL. 491 25 , ERN-ITHACA. 51  n Biosanitaria (IMIB), Mur- , Instituto Murciano de Investigacio 26 , CIBERER Biobank, Valencia, Spain. cia, Spain. 27 n , Laboratorio de Oncología, Pangaea Oncology, Hospital Quiro 52  lica San Antonio, Murcia, Spain. , Universidad Cato 53 Dexeus, Barcelona, Spain. , Endocrinology Department, Hospital Universitari Mútua de 28 , Centro de Investigaciones Biologicas-Margarita Salas (CSIC), Terrassa, Barcelona, Spain. 54 Madrid, Spain. , Institute for Research in Biomedicine (IRB Barcelona), The Bar- 29 n , Department of Genetics, Health Research Institute-Fundacio celona Institute of Science and Technolo-gy (BIST), Laboratory of  noma de Madrid Jiménez Díaz University Hospital, Universidad Auto Amino acid Transporters and Disease, Barcelona, Spain. 55 (IIS-FJD, UAM), Madrid, Spain. , Departamento de Bioquímica, Biología Molecular y Celular, 30 lidos Infantiles, Instituto de Investiga- , Unidad de Tumores So Universidad de Zaragoza, Zaragoza, Spain.  n de Enfermedades Raras, Instituto de Salud Carlos III, cio 56 n Sanitaria (IIS) de Arago , Instituto de Investigacio  n, Zaragoza, Majadahonda, Madrid, Spain. Spain. 31  n de Enfermedades Raras, Instituto de , Instituto de Investigacio 57  n y Física de Sistemas Complejos , Instituto de Biocomputacio Salud Carlos III, Madrid, Spain. (BIFI), Universidad de Zaragoza, Zaragoza, Spain. 32 58 , Biochemistry and Molecular Genetics Department, Hospital , Servicio de Bioquímica, Hospital Universitario 12 de Octubre, Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain. Madrid, Spain. 33 59 , Biochemistry and Molecular Genetics Department, Hospital , Universitat de Vic-Central de Catalunya, Vic, Spain. 60 Clínic de Barcelona, University of Barcelona, Spain. , Genomic Instability and DNA Repair Syndromes Group and 34 , Department of Maternofetal Medicine, Genetics and Repro- Joint Research Unit on Genomic Medicine UAB-Sant Pau Biomed- duction, Institute of Biomedicine of Seville, University Hospital Virgen ical Research Institute (IIB Sant Pau), Institut de Recerca Hospital del Rocío/CSIC/University of Seville, Seville, Spain. de la Santa Creu i Sant Pau-IIB Sant Pau, Barcelona, Spain. 35 61 , Instituto de Biología Molecular de Barcelona (IBMB), CSIC, , Department of Genetics and Microbiology, Universitat Autò- Barcelona, Spain. noma de Barcelona (UAB), Barcelona, Spain. 36 62 , Grupo de Enfermedades Mitocondriales y Neuromusculares, , Gebro Pharma Lab, Barcelona, Spain.  n Hospital 12 de Octubre (imas12), Madrid, Instituto de Investigacio 63 , Centro de Biología Molecular Severo Ochoa, Consejo Superior Spain.  noma de Madrid, de Investigaciones Científicas-Universidad Auto 37  Biomèdica , Neuroimmunology Program, Institut d'Investigacio Madrid, Spain. 64 August Pi i Sunyer (IDIBAPS), Barcelona, Spain. , Unidad Endocrinología, Servicio Pediatría, Hospital Clínico 38 , Hospital Clínic, University of Barcelona, Barcelona, Spain. Universitario ‘Lozano Blesa’, Zaragoza, Spain. 39 65 , Pediatric Neuroinmunology Unit, Sant Joan de Deu Children's , Allergy Department, Hospital Universitario La Paz, Madrid, Hospital, University of Barcelona, Barcelona, Spain. Spain. 40 66 , Genetics Department, Institut de Recerca Sant Joan de Déu, , Research Group on Neuromuscular and Mitochondrial Dis- Barcelona, Spain. eases, Vall d'Hebron Research Institute, Universitat Autònoma de Bar- 41 , Unidad de Genética Clínica y Genética Funcional, Facultad de celona, Barcelona, Spain. 67 Medicina, Universidad de Zaragoza, Spain. , Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospi- 42 , Departamento de Medicina, Universitat de Vic–Universitat tal Universitari, Barcelona, Spain. 68 Central de Catalunya, Vic, Barcelona, Spain. , Departament de Biomedicina, Facultat de Medicina i Ciències 43 , Unidad de Hematología Pediátrica, Hospital de la Santa Creu i de la Salut, Universitat de Barcelona, Barcelona, Spain. 69 Sant Pau, Barcelona, Spain. , Muscle Research and Mitochondrial Function Laboratory, 44 , Institut d'Investigacions Biomèdiques August Pi i Sunyer Faculty of Medicine and Health Sciences-University of Barcelona, (IDIBAPS), Barcelona, Spain. Internal Medicine Department-Hospital Clinic of Barcelona, Bar- 45 , Allergy Service, Hospital General Universitario Gregorio Mar- celona, Spain.  n, Madrid, Spain. año 70 , Instituto de Investigaciones Biomédicas “Alberto Sols”, CSIC- 46  n Health Research Institute (IiGSM), Madrid, , Gregorio Maraño UAM, Madrid, Spain. Spain. 71  n Progreso y Salud (FPS), , Clinical Bioinformatics Area, Fundacio 47 , Departamento Genética, Microbiologia y Estadística, Facultad CDCA, Hospital Virgen del Rocio, Sevilla, Spain. 72 Biología, Universitat de Barcelona, Barcelona, Spain. , Computational Systems Medicine, Institute of Biomedicine of 48 , Institut de Biomedicina Universitat de Barcelona (IBUB), Bar- Seville (IBIS), Hospital Virgen del Rocio, Sevilla, Spain. celona, Spain. 73 n de Biomedicina Epitelial, Centro de Investigaciones , Divisio 49 , Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona,  gicas (CIEMAT), Madrid, Spain. Energéticas, Medioambientales y Tecnolo 74 Spain. , IIS-FJD, Madrid, Spain. 50  n de Genética Médica, Servicio de Pediatría, Hospital , Seccio 75 , Clinical Biochemistry Department, Institut de Recerca Sant Clínico Universitario Virgen de la Arrixaca, Murcia, Spain. Joan de Déu, Barcelona, Spain. 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 492 LUQUE ET AL. 76 103 , Neurometabolic Diseases Laboratory, Bellvitge Biomedical , Lab Neuromuscular diseases, Institut de Recerca Hospital de Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain. la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barce- 77 , Neuromuscular Unit, Neurology Department, Hospital lona, Spain. 104 Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de , Synaptic metabolism laboratory, Institut de Recerca Sant Joan Llobregat, Spain. de Déu, Barcelona, Spain. 78 105 , Grupo de Cáncer Endocrino, Programa de Genética del Cáncer , Division of Dysmorphology and Teratology, Department of  gicas, CNIO Humano, Centro Nacional de Investigaciones Oncolo Pediatrics, University of California San Diego (UCSD), La Jolla, Spain. CA, USA. 79 106 , Departament de Bioquímica i Biología Molecular, Universitat , Division of Genetics, Rady Children's Hospital San Diego, San de València, Burjassot, Spain. Diego, CA, USA. 80 , Estructura de Recerca Interdisciplinar en Biotecnologia i Bio- 107 n y Cajal, , Servicio de Genética, Hospital Universitario Ramo medicina (ERI BIOTECMED), Universitat de València, Burjassot, Spain. IRYCIS, Madrid, Spain. 81 108 , Cruces University Hospital, UPV/EHU, Barakaldo, Spain. , Clinical Immunology Department, La Paz University Hospital 82 , Endo-ERN. and Lymphocyte Pathophysiology in Immunodeficiencies Group, 83 , Biocruces Bizkaia Health Research Institute, Barakaldo, Spain. Madrid, Spain. 84 109 , Centre for Biomedical Network Research Diabetes and Associ- , Universidad Carlos III de Madrid, Departamento de Bio- ated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, ingeniería e Ingeniería Aeroespacial, Madrid, Spain. Madrid, Spain. 110  stico de Enfermedades Moleculares, Centro , Centro de Diagno 85 , Pediatric Hematology and Oncology departments, Hospital noma de Madrid, Madrid, de Biología Molecular, Universidad Auto Sant Joan de Deú, Barcelona, Spain. Spain. 86 111 , Institut de Recerca Sant Joan de Déu, Barcelona, Spain. , Universitat Pompeu Fabra (UPF), Barcelona, Spain. 87 112 , Grupo de Telomerasa, Cáncer y Envejecimiento, Hospital Clí- , Servicio de Neurología, Unidad de Enfermedades nico Universitario Virgen de la Arrixaca, Murcia, Spain. Neuromusculares, Hospital Universitario 12 de Octubre, Madrid, 88 , Department of Animal Medicine and Surgery, Complutense Spain. 113 University of Madrid, Madrid, Spain. , Universidad Carlos III de Madrid, Departamento de Bio- 89 , Instituto de Biomedicina de Valencia, Consejo Superior de ingeniería e Ingeniería Aeroespacial, Madrid, Spain. Investigaciones Científicas (IBV-CSIC), Valencia, Spain. 114 fica (ELA-ALS), Instituto , Unidad de Eclerosis Lateral Amiotro 90 , Laboratorio de Reconocimiento Molecular, Centro de Investi-  n Hospital 12 de Octubre (imas12), Madrid, Spain. de Investigacio n Príncipe Felipe, Valencia, Spain. gacio 115 , Unitat de Fisiologia, Department de Ciències Fisiològiques, 91 , Department of Clinical and Molecular Genetics, Hospital Vall IDIBELL-Institut de Neurociències, Universitat de Barcelona, L'Hospi- d'Hebron, Barcelona, Spain. talet, Spain. 92 116 , Anatomy and Embriology Department, Faculty of Veterinary, , Neuropediatrics Department, Institut de Recerca Sant Joan Universidad Complutense de Madrid, Madrid, Spain. de Déu, Barcelona, Spain. 93 117 , Department of Genetics, Microbiology and Statistics, , Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain. Universitat de Barcelona, Barcelona, Spain. 94 118 , Servicio de Hematología y Oncología Médica, Hospital , Cancer Epigenetics and Nanomedicine Laboratory, Depart-  n, Universitario Morales Meseguer, Centro Regional de Hemodonacio ment of Organisms and Systems Biology, Nanomaterials and Nano- Universidad de Murcia, Murcia, Spain. technology Research Center (CINN-CSIC), Health Research Institute 95 , Servicio de Fisiopatologia Celular y Bioenergética, Universidad of Asturias (ISPA), Institute of Oncology of Asturias (IUOPA), Univer- Pablo de Olavide, Sevilla, Spain. sity of Oviedo, Oviedo, Spain. 96 , Centro Andaluz de Biología del Desarrollo, Universidad Pablo 119  n Sanitaria La Fe, Valencia, Spain. , Instituto de Investigacio 120 de Olavide-CSIC-JA, Sevilla, Spain. , Department of Physiology, Faculty of Medicine and Den- 97 , School of Medicine and Health Sciences, Universitat Inter- tistry, Universitat de València, Valencia, Spain. 121 nacional de Catalunya, Barcelona, Spain. , Biomedical Research Institute INCLIVA, Valencia, Spain. 98 122 , BCNatal-Fetal Medicine Research Center (Hospital Clínic and , Department of Biotechnology, Polytechnic University of Hospital Sant Joan de Déu, University of Barcelona), Barcelona, Spain. Valencia, Valencia, Spain. 99  n Hospital 12 de Octubre (i + 12), , Instituto de Investigacio 123 , Servicio de Pediatría, CSUR Errores Congénitos del Madrid, Spain. Metabolismo, Hospital Universitario 12 de Octubre, Madrid, Spain. 100 , Service of Neurology, Hospital Clínic, Barcelona, Spain. 124  d'Errors Congènits del Metabolisme–IBC, Servei de , Seccio 101 , Centre for Genomic Regulation (CRG), The Barcelona Insti- Bioquímica i Genètica Molecular, Hospital Clínic de Barcelona, Barce- tute of Science and Technology (BIST), Barcelona, Spain. lona, Spain. 102  Catalana de Recerca i Estudis Avançats (ICREA), , Institucio 125 , Pediatric Research and Metabolism Unit, Reina Sofia Univer- Barcelona, Spain. rdoba, Spain. sity Hospital, Co 13990004, 2022, 5-6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cge.14113 by Readcube (Labtiva Inc.), Wiley Online Library on [23/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LUQUE ET AL. 493 126 nides Institute for Biomedical Research of Co , Maimo  rdoba 145 , Unidad de Cáncer Familiar, Programa de Genética del Cáncer  rdoba, Spain. (IMIBIC), Co gicas (CNIO), Humano, Centro Nacional de Investigaciones Oncolo 127  rdoba, Co , University of Co  rdoba, Spain. Madrid, Spain. 128 146 , Departamento de Pediatría, Universidad de Murcia (UMU), , Oncology Department, Hospital de la Santa Creu i Sant Pau, Murcia, Spain. Barcelona, Spain. 129 , Department of Experimental and Health Sciences, Universitat 147  Dexeus Salut de la Dona, Barcelona, Spain. , Fundacio 148 Pompeu Fabra, Barcelona, Spain. , Departament de Psicología Clínica i de la Salut, Universitat 130 , Neuromuscular Unit, Institut de Recerca Sant Joan de Déu, Autònoma de Barcelona, Bellaterra, Barcelona, Spain. 149 Barcelona, Spain. , Dermatology Department, Melanoma Unit, Hospital Clínic 131 , Pathology Department, Institut de Recerca Sant Joan de Déu, Barcelona, Barcelona, Spain. 150 Barcelona, Spain. , Molecular Biology CORE, Biomedical Diagnostic Center 132 , Department of Otorhinolaryngology, La Paz University Hospi- (CDB), Hospital Clínic de Barcelona, University of Barcelona, Barce- tal, Madrid, Spain. lona, Spain. 133  mica Funcional, Facultad , Unidad de Genética Clínica y Geno 151 , Unidad de Genética Clínica, Servicio de Pediatría, Hospital de Medicina, Universidad de Zaragoza, Zaragoza, Spain. Clínico Universitario “Lozano Blesa”, Zaragoza, Spain. 134 152 , Centro Comunitario de Sangre y Tejidos del Principado de , Reproductive Genetics Unit, IVI, Madrid, Spain. 153 Asturias, Oviedo, Spain. , Pharmacy Department, Hospital de la Santa Creu i Sant Pau, 135 n de Biomedicina Epitelial, Centro de Investigaciones , Divisio Barcelona, Spain.  gicas (UNIDAD MIXTA Energéticas, Medioambientales y Tecnolo 154 , Pediatric Neurology Unit, Department of Pediatrics, Hospital CCST-PA CIEMAT), Madrid, Spain. Universitari Germans Trias i Pujol, Universitat Autònoma de Barce- 136 , Pediatric Neurology Unit, Department of Pediatrics, Univer- lona, Catalonia, Spain.  rdoba, Spain. sity Hospital Reina Sofía, Co 155 , Molecular Biology and Biochemistry Research Centre for 137 , Dept, de Genètica, Microbiologia i Estadística, Universitat de Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut Barcelona, Barcelona, Spain. de Recerca, Universitat Autònoma de Barcelona, Barcelona, 138 , Molecular Genetics, Instituto de n Investigacio de Spain. 156 Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, , BCNatal - Fetal Medicine Research Center (Hospital Clínic and Spain. Hospital Sant Joan de Déu, University of Barcelona), Barcelona, Spain. 139 157 , Department of Fundamental and Medical-Surgical Nursing, , Hospital Universitario de Canarias, Universidad de La Laguna, School of Nursing, Faculty of Medicine and Health Sciences, Santa Cruz de Tenerife, Spain. 158 Universitat de Barcelona, Barcelona, Spain. , Quantitative Genomic Medicine Laboratories (qGenomics), 140 , Department of Molecular Biology and Biochemistry, Univer- Esplugues del Llobregat, Spain. 159 sity of Málaga, Málaga, Spain. , Epilepsy Unit, Neurology Service, Hospital Universitario and 141 , Institute of Biomedical Research in Málaga (IBIMA), Málaga, Spain. n Jiménez Díaz, Madrid, Spain. IIS Fundacio 142 160 , Biochemistry Section, Faculty of Biochemistry and Environ- , Neuromuscular & Ataxias Research group, Instituto de Inves- mental Sciences and Regional Centre for Biomedical Research, n Sanitaria La Fe, Valencia, Spain. tigacio 161 Universidad de Castilla-La Mancha, Toledo, Spain. , University of Valencia School of Medicine, Valencia, Spain. 143 162 , Departamento de Biología Celular e Histología, Facultad de , Servicio de Genética Clínica y Molecular, Hospital Val Biología, Universidad de Murcia, Murcia, Spain. d'Hebron, Barcelona, Spain. 144 163 , Instituto de Neurociencias (CSIC-UMH), Sant Joan d'Alacant, , Skeletal dysplasia multidisciplinary Unit (UMDE), ERN-BOND, Spain. Hospital Universitario la Paz, Madrid, Spain.