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Background Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants. Results Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/. Conclusion SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation 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 Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, 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., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation 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 Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, 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. This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variabilityworldwide. CSVS is also part of the GA4GH Beacon network., Spanish Ministry of Economy and Competitiveness SAF2017-88908-R PT17/0009/0006 PI19/00321 CIBERER ACCI-06/07/0036 PI14-948 PI171659, Regional Government of Madrid, RAREGenomicsCM B2017/BMD3721 B2017/BMD-3721, European Union (EU), European Union (EU) 676559, University Chair UAM-IIS-FJD of Genomic Medicine, Ramon Areces Foundation

Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Treatment", celebrado en California (USA) del 12 al 14 de enero de 2016., Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO). Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g BW/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex and striatum. Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO. Deiodinase 1 activity and gene expression in the liver increased while it did not have any effect in the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in striatum. Direct measures of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC. Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on the gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.

Resumen del póster presentado al VII Congreso Internacional de Medicamentos Huérfanos y Enfermedades Raras: "Consolidando esfuerzos: Una responsabilidad compartida”, celebrado en Sevilla (España) del 12 al 14 de febrero de 2015., The Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the monocarboxylate transporter 8 (MCT8) which is a thyroid hormone (TH)-specific cell membrane transporter. Mutations in MCT8 lead to profound psychomotor retardation and abnormal serum TH levels with low T4 and high T3. In contrast to this peripheral hyperthyroidism, the brain shows signs of hypothyroidism. Currently, therapeutic options for patients are limited. The acetic acid derivative of T3, TRIAC, has potential therapeutic value. Here we have analysed the in vivo effects of TRIAC in wild type (WT) and Mct8 knockout (KO) mice after administration of 30 ng/g bw/day in the drinking water from P21 to P30. TRIAC, T4 and T3 were measured by specific RIAs. Serum TRIAC increased and reached the same concentration in WT and Mct8KO after treatment. TRIAC treatment greatly decreased serum T4 in the WT and the Mct8KO, and decreased T3 to normal levels in the Mct8KO which could ameliorate hyperthyroidism in patients. Also at a peripheral level TRIAC increased liver Dio1 activity and mRNA in both genotypes and Serca2a, a TH-dependent gene in the heart, was not affected by any of the experimental conditions. Effect of TRIAC in brain was assessed by the expression of TH-dependent genes: Hr, Cbr2, Itih3, and Flywch2 in the cerebral cortex. Expression analysis suggest that TRIAC treatment induces a state of hypothyroxinemia that at least in brain is partially compensated by its thyromimetic actions. Furthermore, Hr expression in hypothyroid WT and hypothyroid Mct8KO animals is severely decreased and increases after treatment in both conditions providing direct evidence of the regulation of gene expression by TRIAC. The amelioration of the peripheral hyperthyroidism and the potential action in brain gene expression suggest that TRIAC could be a promising treatment for the AHDS.

Resumen del trabajo presentado al MCT8 Symposium celebrado del 12 al 14 de enero de 2015 en California (USA)., In the 2013 MCT8 symposium we presented data on the pathology of MCT8-deficient brain, showing histological alterations compatible with impaired TH action during neural development. Mechanisms of TH transport and their interaction with deiodinases in the developing human brain are poorly understood. In rodents Mct8 is present in the BBB, the neural cell membranes, and the choroid plexus, and Oatp1c1 is present in the BBB, the astrocytes, the choroid plexus and the ventricular surface. D2 is present in glial cells and D3 in neurons. Understanding how all these factors interact is essential to understand the pathophysiological mechanisms in MCT8 deficiency. In this presentation we will show that in the human fetus MCT8 is expressed in brain vessels, and also in the ependimocytes and the radial glia. D3 immunoreactivity is also present in the radial glia. DIO2 mRNA is expressed in the developing cortex, probably in the radial glia, but this awaits confirmation. The data suggest additional transport routes whereby the radial glia regulates the amounts of T4 and T3 available to the developing cortex. Future directions will include the analysis of this process in more detail by correlating the expression of transporters and deiodinases in the developing human brain at different stages of maturation, and looking for its correlate in the mouse brain.