Characterization of the Common Genetic Variation in the Spanish Population of Navarre.

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.

Primary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel RPGR Variant and Possible Modifier Gene.

We report a novel RPGR 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 RPGR 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 RPGR 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' nasal brushing samples. In addition, a missense variant in CEP290 was identified. The concurrent RPGR 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's pathogenicity was confirmed, although it alone does not explain the respiratory symptoms. Finally, the CEP290 gene may be a potential modifier for respiratory symptoms in patients with RPGR mutations.

A crowdsourcing database for the copy-number variation of the Spanish population.

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.

Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.

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, ßAPRIL, 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 (rs = 0.67, p ≤ 0.001) and ßAPRIL 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.

Accesibilidad en la alimentación en personas mayores / Accessibility in food for older people / Acessibilidade alimentar em idosos

La alimentación adecuada es un derecho humano que contribuye a una buena calidad de vida de las personas y uno de sus componentes básicos es la accesibilidad. En el Plan de cuidados de Enfermería, se valora el proceso de envejecimiento y las modificaciones que éste genera pudiendo contribuir a situaciones de vulnerabilidad desde el punto de vista nutricional. La accesibilidad a la alimentación se puede ver afectada por diferentes factores, como es el acceso físico, alimentos suficientes y adecuados, y las dificultades económicas. El objetivo fue conocer la accesibilidad en la alimentación de personas mayores (65 años y más) que residen en complejos habitacionales para jubilados y pensionistas. Se realizó un estudio de tipo cuantitativo de corte transversal. La recolección de los datos se llevó a cabo en tres complejos habitacionales para jubilados y pensionistas, seleccionados dos de ellos en la ciudad de Montevideo y uno en la ciudad de Rivera. La muestra estuvo conformada por 68 personas (69% de los residentes) que residen en los complejos.Los resultados demuestran que un 18% de esta población tiene dificultades en la accesibilidad en la alimentación, las causas fueron la falta de dinero en un 70% y un 30% por problema en la movilidad. Es reconocido en Uruguay el derecho a la alimentación y en generar políticas públicas y programas que contribuyan a satisfacer esta necesidad vital y garantizar el acceso a la misma, en grupos de población vulnerables como puede ser en las personas mayores.

Adequate food is a human right that contributes to a good quality of life for people and one of its basic components is accessibility. In the Nursing Care Plan, the aging process and the changes it generates are valued and may contribute to situations of vulnerability from the nutritional point of view. Accessibility to food can be affected by different factors, such as physical access, sufficient and adequate food, and economic difficulties. The objective was to know the accessibility in food of older people (65 years and over) who reside in housing complexes for retirees and pensioners. A quantitative cross-sectional study was carried out. Data collection was carried out in three housing complexes for retirees and pensioners, two of them selected in the city of Montevideo and one in the city of Rivera. The sample consisted of 68 people (69% of the residents) who reside in the complexes. The results show that 18% of this population has difficulties in food accessibility, the causes were lack of money in 70% and 30% due to mobility problems. The right to food is recognized in Uruguay and to generate public policies and programs that contribute to satisfying this vital need and guaranteeing access to it, in vulnerable population groups such as the elderly.

A alimentação adequada é um direito humano que contribui para uma boa qualidade de vida das pessoas e um de seus componentes básicos é a acessibilidade. No Plano de Assistência de Enfermagem, o processo de envelhecimento e as mudanças que ele gera são valorizados e podem contribuir para situações de vulnerabilidade do ponto de vista nutricional. A acessibilidade aos alimentos pode ser afetada por diversos fatores, como acesso físico, alimentação suficiente e adequada e dificuldades econômicas. O objetivo foi conhecer a acessibilidade na alimentação de pessoas idosas (65 anos ou mais) que residem em conjuntos habitacionais para aposentados e pensionistas. Foi realizado um estudo quantitativo transversal. A coleta de dados foi realizada em três conjuntos habitacionais para aposentados e pensionistas, dois deles selecionados na cidade de Montevidéu e um nacidade de Rivera. A amostra foi composta por 68 pessoas (69% dos moradores) que residem nos complexos. Os resultados mostram que 18% dessa população tem dificuldades na acessibilidade alimentar, as causas foram falta de dinheiro em 70% e 30% por problemas de locomoção. O direito à alimentação é reconhecido no Uruguai e para gerar políticas e programas públicos que contribuam para satisfazer esta necessidade vital e garantir o acesso a ela, em grupos populacionais vulneráveis como os idosos.

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

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.

CSVS, a crowdsourcing database of the Spanish population genetic variability.

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/.

SMN1 copy-number and sequence variant analysis from next-generation sequencing data.

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.

Emerging BCR/ABL1 Mutations Under Treatment with Tyrosine Kinase Inhibitors in Paediatric Acute Lymphoblastic Leukaemia.

We report on the emergence and clinical relevance of an unusual BCR-ABL1 kinase domain mutational status in a 2-year-old female with p210-BCR-ABL Philadelphia chromosome-positive acute lymphoblastic leukaemia. We detected three BCR-ABL1 clones determined by the presence of the E255V, D276G and F317L mutations. We point out the usefulness of searching for mutated populations that survive tyrosine-kinase inhibitor therapy and the role of their clonal selection over time in relation to therapeutic intervention.

Tuberculose peritoneal na infância: relato de um caso / Tuberculous peritonitis: case report

Os autores descrevem o caso de um paciente de 14 anos com tuberculose peritoneal, admitido no hospital com queixa de ascite, perda de peso, febre de baixa intensidade, dor abdominal e história de tratamento de esquistossomose mansônica. ao exame físico, o paciente apresentava-se pálido com abdome tenso, e circulaçÝo colateral superficial. Nos exames laboratoiais: Hemoglobina14g5, leuc[ocitos 6700/mm3. a contagem diferencial revelou apenas eosinofilia, 145. Os valores de bilirrubina, transaminases, protidograma e fosfatase alcalina foram normais. Uma telerradiografia do tórax mostrou infiltrado hilar. Um teste tuberculínico de Mantoux resultou em 15mm(reator forte). Cultura de escarro e líquido ascítico para BK foram negativos. O nível de proteínas totais do líquido ascítico mostrou-se elevado. O paciente foi tratado com sucesso para tuberculose abdominal, com esquema tríplice