@article {816, title = {Characterization of the Common Genetic Variation in the Spanish Population of Navarre.}, journal = {Genes (Basel)}, volume = {15}, year = {2024}, month = {2024 May 04}, abstract = {

Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35\% classified as common (MAF > 1\%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF <= 1\%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.

}, keywords = {Cohort Studies, Exome, Female, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Humans, Male, Polymorphism, Single Nucleotide, Spain, Whole Genome Sequencing}, issn = {2073-4425}, doi = {10.3390/genes15050585}, author = {Maillo, Alberto and Huergo, Estefania and Apell{\'a}niz-Ruiz, Mar{\'\i}a and Urrutia-Lafuente, Edurne and Miranda, Mar{\'\i}a and Salgado, Josefa and Pasalodos-Sanchez, Sara and Delgado-Mora, Luna and Teijido, {\'O}scar and Goicoechea, Ibai and Carmona, Rosario and Perez-Florido, Javier and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Pe{\~n}a-Chilet, Maria and Beltran, Sergi and Dopazo, Joaquin and Lasa, I{\~n}igo and Beloqui, Juan Jos{\'e} and Alonso, {\'A}ngel and Gomez-Cabrero, David} } @article {806, title = {Primary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel Variant and Possible Modifier Gene.}, journal = {Cells}, volume = {13}, year = {2024}, month = {2024 Mar 16}, abstract = {

We report a novel missense variant co-segregated with a familial X-linked retinitis pigmentosa (XLRP) case. The brothers were hemizygous for this variant, but only the proband presented with primary ciliary dyskinesia (PCD). Thus, we aimed to elucidate the role of the variant and other modifier genes in the phenotypic variability observed in the family and its impact on motile cilia. The pathogenicity of the variant on the RPGR protein was evaluated by in vitro studies transiently transfecting the mutated gene, and immunofluorescence analysis on nasal brushing samples. Whole-exome sequencing was conducted to identify potential modifier variants. In vitro studies showed that the mutated RPGR protein could not localise to the cilium and impaired cilium formation. Accordingly, RPGR was abnormally distributed in the siblings{\textquoteright} nasal brushing samples. In addition, a missense variant in was identified. The concurrent variant influenced ciliary mislocalisation of the protein. We provide a comprehensive characterisation of motile cilia in this XLRP family, with only the proband presenting PCD symptoms. The variant{\textquoteright}s pathogenicity was confirmed, although it alone does not explain the respiratory symptoms. Finally, the gene may be a potential modifier for respiratory symptoms in patients with mutations.

}, keywords = {Ciliary Motility Disorders, Eye Proteins, Genes, Modifier, Humans, Male, mutation, Retinitis pigmentosa}, issn = {2073-4409}, doi = {10.3390/cells13060524}, author = {Baz-Red{\'o}n, Noelia and S{\'a}nchez-Bellver, Laura and Fern{\'a}ndez-Cancio, M{\'o}nica and Rovira-Amigo, Sandra and Burgoyne, Thomas and Ranjit, Rai and Aquino, Virginia and Toro-Barrios, Noem{\'\i} and Carmona, Rosario and Polverino, Eva and Cols, Maria and Moreno-Gald{\'o}, Antonio and Camats-Tarruella, N{\'u}ria and Marfany, Gemma} } @article {769, title = {A crowdsourcing database for the copy-number variation of the Spanish population.}, journal = {Hum Genomics}, volume = {17}, year = {2023}, month = {2023 Mar 09}, pages = {20}, abstract = {

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.

}, issn = {1479-7364}, doi = {10.1186/s40246-023-00466-8}, author = {L{\'o}pez-L{\'o}pez, Daniel and Rold{\'a}n, Gema and Fernandez-Rueda, Jose L and Bostelmann, Gerrit and Carmona, Rosario and Aquino, Virginia and Perez-Florido, Javier and Ortuno, Francisco and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Gonz{\'a}lez-Neira, Anna and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {759, title = {Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jul 02}, pages = {11219}, abstract = {

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60~years old) of 100 patients (48\% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p <= 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p <= 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

}, issn = {2045-2322}, doi = {10.1038/s41598-022-15549-0}, author = {Ortiz-Aljaro, Pilar and Montes-Cano, Marco Antonio and Garc{\'\i}a-Lozano, Jos{\'e}-Ra{\'u}l and Aquino, Virginia and Carmona, Rosario and Perez-Florido, Javier and Garc{\'\i}a-Hern{\'a}ndez, Francisco Jos{\'e} and Dopazo, Joaquin and Gonz{\'a}lez-Escribano, Mar{\'\i}a Francisca} } @article {701, title = {CSVS, a crowdsourcing database of the Spanish population genetic variability.}, journal = {Nucleic Acids Res}, volume = {49}, year = {2021}, month = {2021 01 08}, pages = {D1130-D1137}, abstract = {

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 variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

}, keywords = {Alleles, Chromosome Mapping, Crowdsourcing, Databases, Genetic, Exome, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Internet, Precision Medicine, Software, Spain}, issn = {1362-4962}, doi = {10.1093/nar/gkaa794}, author = {Pe{\~n}a-Chilet, Maria and Rold{\'a}n, Gema and Perez-Florido, Javier and Ortuno, Francisco M and Carmona, Rosario and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Fernandez-Rueda, Jose L and Gallego, Asunci{\'o}n and Garcia-Garcia, Francisco and Gonz{\'a}lez-Neira, Anna and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Santoyo-L{\'o}pez, Javier and Ayuso, Carmen and Minguez, Pablo and Avila-Fernandez, Almudena and Corton, Marta and Moreno-Pelayo, Miguel {\'A}ngel and Morin, Mat{\'\i}as and Gallego-Martinez, Alvaro and Lopez-Escamez, Jose A and Borrego, Salud and Anti{\v n}olo, Guillermo and Amigo, Jorge and Salgado-Garrido, Josefa and Pasalodos-Sanchez, Sara and Morte, Beatriz and Carracedo, {\'A}ngel and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {731, title = {De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {877-883}, abstract = {

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

}, keywords = {Child, Preschool, Cytoskeletal Proteins, Dwarfism, Exons, Gene Expression Regulation, Genetic Association Studies, Humans, Male, Neurodevelopmental Disorders, Protein Isoforms, RNA, Messenger, Sequence Deletion, Syndrome, Transcription Factors, Transcription Initiation Site, Transcription, Genetic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62017}, author = {Martinez-Delgado, Beatriz and Lopez-Martin, Estrella and Lara-Herguedas, Juli{\'a}n and Monzon, Sara and Cuesta, Isabel and Juli{\'a}, Miguel and Aquino, Virginia and Rodriguez-Martin, Carlos and Damian, Alejandra and Gonzalo, Irene and Gomez-Mariano, Gema and Baladron, Beatriz and Cazorla, Rosario and Iglesias, Gema and Roman, Enriqueta and Ros, Purificacion and Tutor, Pablo and Mellor, Susana and Jimenez, Carlos and Cabrejas, Maria Jose and Gonzalez-Vioque, Emiliano and Alonso, Javier and Bermejo-S{\'a}nchez, Eva and Posada, Manuel} } @article {705, title = {SMN1 copy-number and sequence variant analysis from next-generation sequencing data.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2073-2077}, abstract = {

Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.

}, keywords = {Base Sequence, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans, Reproducibility of Results, Software, Survival of Motor Neuron 1 Protein}, issn = {1098-1004}, doi = {10.1002/humu.24120}, author = {L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Carmona, Rosario and Aquino, Virginia and Salgado, Josefa and Pasalodos, Sara and Miranda, Mar{\'\i}a and Alonso, {\'A}ngel and Dopazo, Joaquin} }