<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Méndez-Vidal, Cristina</style></author><author><style face="normal" font="default" size="100%">Bravo-Gil, Nereida</style></author><author><style face="normal" font="default" size="100%">Perez-Florido, Javier</style></author><author><style face="normal" font="default" size="100%">Marcos-Luque, Irene</style></author><author><style face="normal" font="default" size="100%">Fernández, Raquel M</style></author><author><style face="normal" font="default" size="100%">Fernandez-Rueda, Jose Luis</style></author><author><style face="normal" font="default" size="100%">González-del Pozo, María</style></author><author><style face="normal" font="default" size="100%">Martín-Sánchez, Marta</style></author><author><style face="normal" font="default" size="100%">Fernández-Suárez, Elena</style></author><author><style face="normal" font="default" size="100%">Mena, Marcela</style></author><author><style face="normal" font="default" size="100%">Carmona, Rosario</style></author><author><style face="normal" font="default" size="100%">Dopazo, Joaquin</style></author><author><style face="normal" font="default" size="100%">Borrego, Salud</style></author><author><style face="normal" font="default" size="100%">Antiňolo, Guillermo</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">A genomic strategy for precision medicine in rare diseases: integrating customized algorithms into clinical practice.</style></title><secondary-title><style face="normal" font="default" size="100%">J Transl Med</style></secondary-title><alt-title><style face="normal" font="default" size="100%">J Transl Med</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Algorithms</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genomics</style></keyword><keyword><style  face="normal" font="default" size="100%">High-Throughput Nucleotide Sequencing</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Precision Medicine</style></keyword><keyword><style  face="normal" font="default" size="100%">rare diseases</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2025</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2025 Jan 20</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">23</style></volume><pages><style face="normal" font="default" size="100%">86</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;Despite the use of Next-Generation Sequencing (NGS) as the gold standard for the diagnosis of rare diseases, its clinical implementation has been challenging, limiting the cost-effectiveness of NGS and the understanding, control and safety essential for decision-making in clinical applications. Here, we describe a personalized NGS-based strategy integrating precision medicine into a public healthcare system and its implementation in the routine diagnosis process during a five-year pilot program.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;Our approach involved customized probe designs, the generation of virtual panels and the development of a personalized medicine module (PMM) for variant prioritization. This strategy was applied to 6500 individuals including 6267 index patients and 233 NGS-based carrier screenings.&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;Causative variants were identified in 2061 index patients (average 32.9%, ranging from 12 to 62% by condition). Also, 131 autosomal-recessive cases could be partially genetically diagnosed. These results led to over 5000 additional studies including carrier, prenatal and preimplantational tests or pharmacological and gene therapy treatments.&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSION: &lt;/b&gt;This strategy has shown promising improvements in the diagnostic rate, facilitating timely diagnosis and gradually expanding our services portfolio for rare diseases. The steps taken towards the integration of clinical and genomic data are opening new possibilities for conducting both retrospective and prospective healthcare studies. Overall, this study represents a major milestone in the ongoing efforts to improve our understanding and clinical management of rare diseases, a crucial area of medical research and care.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">González-del Pozo, María</style></author><author><style face="normal" font="default" size="100%">Méndez-Vidal, Cristina</style></author><author><style face="normal" font="default" size="100%">Bravo-Gil, Nereida</style></author><author><style face="normal" font="default" size="100%">Vela-Boza, Alicia</style></author><author><style face="normal" font="default" size="100%">Dopazo, Joaquin</style></author><author><style face="normal" font="default" size="100%">Borrego, Salud</style></author><author><style face="normal" font="default" size="100%">Antiňolo, Guillermo</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.</style></title><secondary-title><style face="normal" font="default" size="100%">PLoS One</style></secondary-title><alt-title><style face="normal" font="default" size="100%">PLoS One</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adolescent</style></keyword><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Amino Acid Sequence</style></keyword><keyword><style  face="normal" font="default" size="100%">Base Sequence</style></keyword><keyword><style  face="normal" font="default" size="100%">Child</style></keyword><keyword><style  face="normal" font="default" size="100%">Chromosome Segregation</style></keyword><keyword><style  face="normal" font="default" size="100%">DNA Mutational Analysis</style></keyword><keyword><style  face="normal" font="default" size="100%">Exome</style></keyword><keyword><style  face="normal" font="default" size="100%">Family</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Inheritance Patterns</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Molecular Sequence Data</style></keyword><keyword><style  face="normal" font="default" size="100%">mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Pedigree</style></keyword><keyword><style  face="normal" font="default" size="100%">Retinal Dystrophies</style></keyword><keyword><style  face="normal" font="default" size="100%">Rhodopsin</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2014</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2014</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">9</style></volume><pages><style face="normal" font="default" size="100%">e116176</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T&gt;C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C&gt;T; p.R681* and c.6088C&gt;T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program. &lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">12</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/25544989?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Fernández, Raquel M</style></author><author><style face="normal" font="default" size="100%">Bleda, Marta</style></author><author><style face="normal" font="default" size="100%">Luzón-Toro, Berta</style></author><author><style face="normal" font="default" size="100%">García-Alonso, Luz</style></author><author><style face="normal" font="default" size="100%">Arnold, Stacey</style></author><author><style face="normal" font="default" size="100%">Sribudiani, Yunia</style></author><author><style face="normal" font="default" size="100%">Besmond, Claude</style></author><author><style face="normal" font="default" size="100%">Lantieri, Francesca</style></author><author><style face="normal" font="default" size="100%">Doan, Betty</style></author><author><style face="normal" font="default" size="100%">Ceccherini, Isabella</style></author><author><style face="normal" font="default" size="100%">Lyonnet, Stanislas</style></author><author><style face="normal" font="default" size="100%">Hofstra, Robert Mw</style></author><author><style face="normal" font="default" size="100%">Chakravarti, Aravinda</style></author><author><style face="normal" font="default" size="100%">Antiňolo, Guillermo</style></author><author><style face="normal" font="default" size="100%">Dopazo, Joaquin</style></author><author><style face="normal" font="default" size="100%">Borrego, Salud</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Pathways systematically associated to Hirschsprung's disease.</style></title><secondary-title><style face="normal" font="default" size="100%">Orphanet J Rare Dis</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Orphanet J Rare Dis</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Hirschsprung Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Polymorphism, Single Nucleotide</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2013</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2013 Dec 02</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">8</style></volume><pages><style face="normal" font="default" size="100%">187</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations. &lt;/p&gt;</style></abstract><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/24289864?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Fernández, Raquel Ma</style></author><author><style face="normal" font="default" size="100%">Bleda, Marta</style></author><author><style face="normal" font="default" size="100%">Núñez-Torres, Rocío</style></author><author><style face="normal" font="default" size="100%">Medina, Ignacio</style></author><author><style face="normal" font="default" size="100%">Luzón-Toro, Berta</style></author><author><style face="normal" font="default" size="100%">García-Alonso, Luz</style></author><author><style face="normal" font="default" size="100%">Torroglosa, Ana</style></author><author><style face="normal" font="default" size="100%">Marbà, Martina</style></author><author><style face="normal" font="default" size="100%">Enguix-Riego, Ma Valle</style></author><author><style face="normal" font="default" size="100%">Montaner, David</style></author><author><style face="normal" font="default" size="100%">Antiňolo, Guillermo</style></author><author><style face="normal" font="default" size="100%">Dopazo, Joaquin</style></author><author><style face="normal" font="default" size="100%">Borrego, Salud</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.</style></title><secondary-title><style face="normal" font="default" size="100%">Orphanet J Rare Dis</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Orphanet J Rare Dis</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Predisposition to Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Genome-Wide Association Study</style></keyword><keyword><style  face="normal" font="default" size="100%">Genotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Hirschsprung Disease</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2012</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2012 Dec 28</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">7</style></volume><pages><style face="normal" font="default" size="100%">103</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.&lt;/p&gt;</style></abstract><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/23270508?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Barragán, Isabel</style></author><author><style face="normal" font="default" size="100%">Borrego, Salud</style></author><author><style face="normal" font="default" size="100%">Pieras, Juan Ignacio</style></author><author><style face="normal" font="default" size="100%">González-del Pozo, María</style></author><author><style face="normal" font="default" size="100%">Santoyo, Javier</style></author><author><style face="normal" font="default" size="100%">Ayuso, Carmen</style></author><author><style face="normal" font="default" size="100%">Baiget, Montserrat</style></author><author><style face="normal" font="default" size="100%">Millán, José M</style></author><author><style face="normal" font="default" size="100%">Mena, Marcela</style></author><author><style face="normal" font="default" size="100%">Abd El-Aziz, Mai M</style></author><author><style face="normal" font="default" size="100%">Audo, Isabelle</style></author><author><style face="normal" font="default" size="100%">Zeitz, Christina</style></author><author><style face="normal" font="default" size="100%">Littink, Karin W</style></author><author><style face="normal" font="default" size="100%">Dopazo, Joaquin</style></author><author><style face="normal" font="default" size="100%">Bhattacharya, Shomi S</style></author><author><style face="normal" font="default" size="100%">Antiňolo, Guillermo</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.</style></title><secondary-title><style face="normal" font="default" size="100%">Hum Mutat</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Hum Mutat</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Amino Acid Sequence</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Case-Control Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">DNA Mutational Analysis</style></keyword><keyword><style  face="normal" font="default" size="100%">Drosophila Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Evolution, Molecular</style></keyword><keyword><style  face="normal" font="default" size="100%">Eye Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Genes, Recessive</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Variation</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Molecular Sequence Data</style></keyword><keyword><style  face="normal" font="default" size="100%">mutation</style></keyword><keyword><style  face="normal" font="default" size="100%">Pedigree</style></keyword><keyword><style  face="normal" font="default" size="100%">Polymorphism, Single Nucleotide</style></keyword><keyword><style  face="normal" font="default" size="100%">Protein Structure, Tertiary</style></keyword><keyword><style  face="normal" font="default" size="100%">Retinitis pigmentosa</style></keyword><keyword><style  face="normal" font="default" size="100%">Spain</style></keyword><keyword><style  face="normal" font="default" size="100%">Structural Homology, Protein</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2010</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2010 Nov</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">31</style></volume><pages><style face="normal" font="default" size="100%">E1772-800</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">11</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/21069908?dopt=Abstract</style></custom1></record></records></xml>