Search

Your search keyword '"Spataro, Nino"' showing total 107 results
Start Over Author "Spataro, Nino"
107 results on '"Spataro, Nino"'

1. Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay

Author

Tan, Senwei, Zhang, Qiumeng, Zhan, Rui, Luo, Si, Han, Yaoling, Yu, Bin, Muss, Candace, Pingault, Veronique, Marlin, Sandrine, Delahaye, Andrée, Peters, Sophia, Perne, Claudia, Kreiß, Martina, Spataro, Nino, Trujillo-Quintero, Juan Pablo, Racine, Caroline, Tran-Mau-Them, Frederic, Phornphutkul, Chanika, Besterman, Aaron D., Martinez, Julian, Wang, Xiuxia, Tian, Xiaoyu, Srivastava, Siddharth, Urion, David K., Madden, Jill A., Saif, Hind Al, Morrow, Michelle M., Begtrup, Amber, Li, Xing, Jurgensmeyer, Sarah, Leahy, Peter, Zhou, Shimin, Li, Faxiang, Hu, Zhengmao, Tan, Jieqiong, Xia, Kun, and Guo, Hui

Published
2024
Full Text
View/download PDF

2. Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome

Author

Manso-Bazús, Carmen, primary, Spataro, Nino, additional, Gabau, Elisabeth, additional, Beltrán-Salazar, Viviana P., additional, Trujillo-Quintero, Juan Pablo, additional, Capdevila, Nuria, additional, Brunet-Vega, Anna, additional, Baena, Neus, additional, Jeyaprakash, A Arockia, additional, Martinez-Glez, Victor, additional, and Ruiz, Anna, additional

Published
2024
Full Text
View/download PDF

3. Elimination of lipaemic interference by high-speed centrifugation

Author

Solé-Enrech, Gemma, Cano-Corres, Ruth, Aparicio-Calvente, Maria Isabel, Spataro, Nino, Solé-Enrech, Gemma, Cano-Corres, Ruth, Aparicio-Calvente, Maria Isabel, and Spataro, Nino

Abstract

IntroductionIn order to deliver high quality results, detection and elimination of possible analytical interferences, such as lipaemia, is crucial. The aim of this study is to evaluate the efficacy of high-speed centrifugation in eliminating lipaemic interference and to define own lipaemic index (LI) for the studied biochemical analytes. Materials and methodsEvaluated analytes were: albumin, alkaline phosphatase, alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), calcium, creatinine, gamma-glutamyltransferase (GGT), glucose, phosphates, total proteins, urea and total bilirubin. Those analytes and LIs have been analysed in duplicate in the Roche Diagnostics-c8000 analyser in samples centrifuged at 3000 rpm/10 minutes in the SL16 (Thermo Scientific, Waltham, USA) centrifuge and according to an own high-speed centrifugation protocol (12,900 rpm/15 minutes) in the MicroCL17R (Thermo Scientific, Waltham, USA) centrifuge. Lipaemia has been measured in each sample. The efficiency of high-speed centrifugation is verified by the Wilcoxon test (P < 0.05). In cases where significant differences are observed, our own LI is calculated. For ALT and AST, it is verified by McNemar test (P < 0.05). For creatinine, both Wilcoxon and McNemar test were applied. ResultsThere were statistically significant differences in analyte concentration before and after high-speed centrifugation for: albumin, creatinine, GGT, glucose, phosphates, urea and total bilirrubin. Own LI is calculated. McNemar test shows statistically significant diferences in the proportion of delivered results before and after high-speed centrifugation in ALT, AST and creatinine. ConclusionsThis study confirms the efficacy of high-speed centrifugation protocol for all the considered analytes, excepting calcium, alkaline phosphatase and total proteins.

Published
2023

4. Monoallelic loss-of-function variants in GSK3Blead to autism and developmental delay

Author

Tan, Senwei, Zhang, Qiumeng, Zhan, Rui, Luo, Si, Han, Yaoling, Yu, Bin, Muss, Candace, Pingault, Veronique, Marlin, Sandrine, Delahaye, Andrée, Peters, Sophia, Perne, Claudia, Kreiß, Martina, Spataro, Nino, Trujillo-Quintero, Juan Pablo, Racine, Caroline, Tran-Mau-Them, Frederic, Phornphutkul, Chanika, Besterman, Aaron D., Martinez, Julian, Wang, Xiuxia, Tian, Xiaoyu, Srivastava, Siddharth, Urion, David K., Madden, Jill A., Saif, Hind Al, Morrow, Michelle M., Begtrup, Amber, Li, Xing, Jurgensmeyer, Sarah, Leahy, Peter, Zhou, Shimin, Li, Faxiang, Hu, Zhengmao, Tan, Jieqiong, Xia, Kun, and Guo, Hui

Abstract

De novo variants adjacent to the canonical splicing sites or in the well-defined splicing-related regions are more likely to impair splicing but remain under-investigated in autism spectrum disorder (ASD). By analyzing large, recent ASD genome sequencing cohorts, we find a significant burden of de novo potential splicing-disrupting variants (PSDVs) in 5048 probands compared to 4090 unaffected siblings. We identified 55 genes with recurrent de novo PSDVs that were highly intolerant to variation. Forty-six of these genes have not been strongly implicated in ASD or other neurodevelopmental disorders previously, including GSK3B. Through international, multicenter collaborations, we assembled genotype and phenotype data for 15 individuals with GSK3Bvariants and identified common phenotypes including developmental delay, ASD, sleeping disturbance, and aggressive behavior. Using available single-cell transcriptomic data, we show that GSK3Bis enriched in dorsal progenitors and intermediate forms of excitatory neurons in the developing brain. We showed that Gsk3bknockdown in mouse excitatory neurons interferes with dendrite arborization and spine maturation which could not be rescued by de novo missense variants identified from affected individuals. In summary, our findings suggest that PSDVs may play an important role in the genetic etiology of ASD and allow for the prioritization of new ASD candidate genes. Importantly, we show that genetic variation resulting in GSK3Bloss-of-function can lead to a neurodevelopmental disorder with core features of ASD and developmental delay.

Published
2024
Full Text
View/download PDF

5. High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders

Author

Spataro, Nino, primary, Trujillo-Quintero, Juan Pablo, additional, Manso, Carmen, additional, Gabau, Elisabeth, additional, Capdevila, Nuria, additional, Martinez-Glez, Victor, additional, Berenguer-Llergo, Antoni, additional, Reyes, Sara, additional, Brunet, Anna, additional, Baena, Neus, additional, Guitart, Miriam, additional, and Ruiz, Anna, additional

Published
2023
Full Text
View/download PDF

6. Elimination of lipaemic interference by high-speed centrifugation

Author

Solé-Enrech, Gemma, Cano-Corres, Ruth, Aparicio-Calvente, Maria Isabel, and Spataro, Nino

Subjects
Biochemistry (medical), Clinical Biochemistry, lipaemia, high-speed centrifugation, lipaemic index
Abstract

IntroductionIn order to deliver high quality results, detection and elimination of possible analytical interferences, such as lipaemia, is crucial. The aim of this study is to evaluate the efficacy of high-speed centrifugation in eliminating lipaemic interference and to define own lipaemic index (LI) for the studied biochemical analytes. Materials and methodsEvaluated analytes were: albumin, alkaline phosphatase, alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), calcium, creatinine, gamma-glutamyltransferase (GGT), glucose, phosphates, total proteins, urea and total bilirubin. Those analytes and LIs have been analysed in duplicate in the Roche Diagnostics-c8000 analyser in samples centrifuged at 3000 rpm/10 minutes in the SL16 (Thermo Scientific, Waltham, USA) centrifuge and according to an own high-speed centrifugation protocol (12,900 rpm/15 minutes) in the MicroCL17R (Thermo Scientific, Waltham, USA) centrifuge. Lipaemia has been measured in each sample. The efficiency of high-speed centrifugation is verified by the Wilcoxon test (P < 0.05). In cases where significant differences are observed, our own LI is calculated. For ALT and AST, it is verified by McNemar test (P < 0.05). For creatinine, both Wilcoxon and McNemar test were applied. ResultsThere were statistically significant differences in analyte concentration before and after high-speed centrifugation for: albumin, creatinine, GGT, glucose, phosphates, urea and total bilirrubin. Own LI is calculated. McNemar test shows statistically significant diferences in the proportion of delivered results before and after high-speed centrifugation in ALT, AST and creatinine. ConclusionsThis study confirms the efficacy of high-speed centrifugation protocol for all the considered analytes, excepting calcium, alkaline phosphatase and total proteins.

Published
2022
Full Text
View/download PDF

8. Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

Author

Dols-Icardo, Oriol, García-Redondo, Alberto, Rojas-García, Ricardo, Borrego-Hernández, Daniel, Illán-Gala, Ignacio, Muñoz-Blanco, José Luís, Rábano, Alberto, Cervera-Carles, Laura, Juárez-Rufián, Alexandra, Spataro, Nino, De Luna, Noemí, Galán, Lucía, Cortes-Vicente, Elena, Fortea, Juan, Blesa, Rafael, Grau-Rivera, Oriol, Lleó, Alberto, Esteban-Pérez, Jesús, Gelpi, Ellen, and Clarimón, Jordi

Published
2018
Full Text
View/download PDF

9. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Author

Genetica Sectie Genoomdiagnostiek, Child Health, Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Challman, Thomas D, Wain, Karen E, Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, Lanpher, Brendan C, Kemppainen, Jennifer L, Innes, Micheil, Kooy, Frank, Meuwissen, Marije, Goldenberg, Alice, Lecoquierre, Francois, Vera, Gabriella, Diderich, Karin E M, Sheidley, Beth, El Achkar, Christelle Moufawad, Park, Meredith, Hamdan, Fadi F, Michaud, Jacques L, Lewis, Ann J, Zweier, Christiane, Reis, André, Wagner, Matias, Weigand, Heike, Journel, Hubert, Keren, Boris, Passemard, Sandrine, Mignot, Cyril, van Gassen, Koen, Brilstra, Eva H, Itzikowitz, Gina, O'Heir, Emily, Allen, Jake, Donald, Kirsten A, Korf, Bruce Richard, Skelton, Tammi, Thompson, Michelle, Robin, Nathaniel H, Rudy, Natasha L, Dobyns, William B, Foss, Kimberly, Zarate, Yuri Alexander, Bosanko, Katherine A, Alembik, Yves, Durand, Benjamin, Tran Mau-Them, Frederic, Ranza, Emmanuelle, Blanc, Xavier, Antonarakis, Stylianos E, McWalter, Kirsty, Torti, Erin, Millan, Francisca, Dameron, Amy, Tokita, Mari, Zimmermann, Michael T, Klee, Eric W, Piton, Amelie, Gerard, Benedicte, Genetica Sectie Genoomdiagnostiek, Child Health, Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Challman, Thomas D, Wain, Karen E, Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, Lanpher, Brendan C, Kemppainen, Jennifer L, Innes, Micheil, Kooy, Frank, Meuwissen, Marije, Goldenberg, Alice, Lecoquierre, Francois, Vera, Gabriella, Diderich, Karin E M, Sheidley, Beth, El Achkar, Christelle Moufawad, Park, Meredith, Hamdan, Fadi F, Michaud, Jacques L, Lewis, Ann J, Zweier, Christiane, Reis, André, Wagner, Matias, Weigand, Heike, Journel, Hubert, Keren, Boris, Passemard, Sandrine, Mignot, Cyril, van Gassen, Koen, Brilstra, Eva H, Itzikowitz, Gina, O'Heir, Emily, Allen, Jake, Donald, Kirsten A, Korf, Bruce Richard, Skelton, Tammi, Thompson, Michelle, Robin, Nathaniel H, Rudy, Natasha L, Dobyns, William B, Foss, Kimberly, Zarate, Yuri Alexander, Bosanko, Katherine A, Alembik, Yves, Durand, Benjamin, Tran Mau-Them, Frederic, Ranza, Emmanuelle, Blanc, Xavier, Antonarakis, Stylianos E, McWalter, Kirsty, Torti, Erin, Millan, Francisca, Dameron, Amy, Tokita, Mari, Zimmermann, Michael T, Klee, Eric W, Piton, Amelie, and Gerard, Benedicte

Published
2022

12. Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Author

Bullich, Gemma, primary, Matalonga, Leslie, additional, Pujadas, Montserrat, additional, Papakonstantinou, Anastasios, additional, Piscia, Davide, additional, Tonda, Raúl, additional, Artuch, Rafael, additional, Gallano, Pia, additional, Garrabou, Glòria, additional, González, Juan R., additional, Grinberg, Daniel, additional, Guitart, Míriam, additional, Laurie, Steven, additional, Lázaro, Conxi, additional, Luengo, Cristina, additional, Martí, Ramon, additional, Milà, Montserrat, additional, Ovelleiro, David, additional, Parra, Genís, additional, Pujol, Aurora, additional, Tizzano, Eduardo, additional, Macaya, Alfons, additional, Palau, Francesc, additional, Ribes, Antònia, additional, Pérez-Jurado, Luis A., additional, Beltran, Sergi, additional, Schlüter, Agatha, additional, Rodriguez-Palmero, Agustí, additional, Cáceres, Alejandro, additional, Nascimento, Andrés, additional, García-Cazorla, Àngels, additional, Cueto-González, Anna, additional, Marcé-Grau, Anna, additional, Nel.lo, Anna Ruiz, additional, Martínez-Monseny, Antonio, additional, Sànchez, Aurora, additional, García, Belén, additional, Pérez-Dueñas, Belén, additional, Gel, Bernat, additional, Fusté, Berta, additional, Hernández-Ferrer, Carles, additional, Casasnovas, Carlos, additional, Ortez, Carlos, additional, Arjona, César, additional, Hernando-Davalillo, Cristina, additional, de Benito, Daniel Natera, additional, Amador, Daniel Picó, additional, Gómez-Andrés, David, additional, Yubero, Dèlia, additional, Pelegrí-Sisó, Dolors, additional, Verdura, Edgard, additional, García-Arumí, Elena, additional, Castellanos, Elisabeth, additional, Gabau, Elisabeth, additional, Tobías, Ester, additional, López-Grondona, Fermina, additional, Cardellach, Francesc, additional, Garcia-Garcia, Francesc Josep, additional, Munell, Francina, additional, Tort, Frederic, additional, Aznar, Gemma, additional, Olivé-Cirera, Gemma, additional, Tell, Gemma, additional, Muñoz-Pujol, Gerard, additional, Paramonov, Ida, additional, Blanco, Ignacio, additional, Madrigal, Irene, additional, Valenzuela, Irene, additional, Gut, Ivo, additional, Cusco, Ivon, additional, Trotta, Jean-Rémi, additional, Cruz, Jordi, additional, Díaz-Manera, Jordi, additional, Milisenda, José César, additional, Ma Grau, Josep, additional, Garcia-Villoria, Judit, additional, Armstrong, Judith, additional, Cantó, Judith, additional, Sala-Coromina, Júlia, additional, Rodríguez-Revenga, Laia, additional, Alias, Laura, additional, Gort, Laura, additional, González-Quereda, Lídia, additional, Costa, Mar, additional, Fernández-Callejo, Marcos, additional, López-Sánchez, Marcos, additional, Álvarez-Mora, Maria Isabel, additional, Gut, Marta, additional, Serrano, Mercedes, additional, Raspall-Chaure, Miquel, additional, Toro, Mireia del, additional, Bayés, Mònica, additional, Díez, Neus Baena, additional, Spataro, Nino, additional, Capdevila, Núria, additional, Ugarteburu, Olatz, additional, Muñoz-Cabello, Patricia, additional, Duque, Penélope Romero, additional, Rabionet, Raquel, additional, Rojas-García, Ricard, additional, Calvo, Rosa, additional, Urreizti, Roser, additional, Bernal, Sara, additional, Boronat, Susana, additional, Balcells, Susanna, additional, and Vendrell, Teresa, additional

Published
2022
Full Text
View/download PDF

13. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, primary, Cousin, Margot A, additional, Dsouza, Nikita R, additional, Challman, Thomas D, additional, Wain, Karen E, additional, Powis, Zoe, additional, Minks, Kelly, additional, Trimouille, Aurélien, additional, Lasseaux, Eulalie, additional, Lacombe, Didier, additional, Angelini, Chloé, additional, Michaud, Vincent, additional, Van-Gils, Julien, additional, Spataro, Nino, additional, Ruiz, Anna, additional, Gabau, Elizabeth, additional, Stolerman, Elliot, additional, Washington, Camerun, additional, Louie, Ray, additional, Lanpher, Brendan C, additional, Kemppainen, Jennifer L, additional, Innes, Micheil, additional, Kooy, Frank, additional, Meuwissen, Marije, additional, Goldenberg, Alice, additional, Lecoquierre, Francois, additional, Vera, Gabriella, additional, Diderich, Karin E M, additional, Sheidley, Beth, additional, El Achkar, Christelle Moufawad, additional, Park, Meredith, additional, Hamdan, Fadi F, additional, Michaud, Jacques L, additional, Lewis, Ann J, additional, Zweier, Christiane, additional, Reis, André, additional, Wagner, Matias, additional, Weigand, Heike, additional, Journel, Hubert, additional, Keren, Boris, additional, Passemard, Sandrine, additional, Mignot, Cyril, additional, van Gassen, Koen, additional, Brilstra, Eva H, additional, Itzikowitz, Gina, additional, O'Heir, Emily, additional, Allen, Jake, additional, Donald, Kirsten A, additional, Korf, Bruce Richard, additional, Skelton, Tammi, additional, Thompson, Michelle, additional, Robin, Nathaniel H, additional, Rudy, Natasha L, additional, Dobyns, William B, additional, Foss, Kimberly, additional, Zarate, Yuri Alexander, additional, Bosanko, Katherine A, additional, Alembik, Yves, additional, Durand, Benjamin, additional, Tran Mau-them, Frederic, additional, Ranza, Emmanuelle, additional, Blanc, Xavier, additional, Antonarakis, Stylianos E, additional, McWalter, Kirsty, additional, Torti, Erin, additional, Millan, Francisca, additional, Dameron, Amy, additional, Tokita, Mari, additional, Zimmermann, Michael T, additional, Klee, Eric W, additional, Piton, Amelie, additional, and Gerard, Benedicte, additional

Published
2021
Full Text
View/download PDF

14. New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

Author

Aguilera, Cinthia, primary, Gabau, Elisabeth, additional, Ramirez-Mallafré, Ariadna, additional, Brun-Gasca, Carme, additional, Dominguez-Carral, Jana, additional, Delgadillo, Veronica, additional, Laurie, Steve, additional, Derdak, Sophia, additional, Padilla, Natàlia, additional, de la Cruz, Xavier, additional, Capdevila, Núria, additional, Spataro, Nino, additional, Baena, Neus, additional, Guitart, Miriam, additional, and Ruiz, Anna, additional

Published
2021
Full Text
View/download PDF

17. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.

Author

Schalk, Audrey, Cousin, Margot A., Dsouza, Nikita R., Challman, Thomas D., Wain, Karen E., Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, and Lanpher, Brendan C.

Abstract

Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in- frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene- silencing pathways mediated by small non- coding RNAs. Three- dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestation Conclusion Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

18. Genome-phenome explorer (GePhEx): a tool for the visualization and interpretation of phenotypic relationships supported by genetic evidence

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Instituto de Salud Carlos III, Instituto Nacional de Bioinformática (España), Red Española de Esclerosis Múltiple, Farré, Xavier, Spataro, Nino, Haziza, Frederic, Rambla, Jordi, Navarro, Arcadi, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Generalitat de Catalunya, Instituto de Salud Carlos III, Instituto Nacional de Bioinformática (España), Red Española de Esclerosis Múltiple, Farré, Xavier, Spataro, Nino, Haziza, Frederic, Rambla, Jordi, and Navarro, Arcadi

Abstract

[Motivation] Association studies based on SNP arrays and Next Generation Sequencing technologies have enabled the discovery of thousands of genetic loci related to human diseases. Nevertheless, their biological interpretation is still elusive, and their medical applications limited. Recently, various tools have been developed to help bridging the gap between genomes and phenomes. To our knowledge, however none of these tools allows users to retrieve the phenotype-wide list of genetic variants that may be linked to a given disease or to visually explore the joint genetic architecture of different pathologies., [Results] We present the Genome-Phenome Explorer (GePhEx), a web-tool easing the visual exploration of phenotypic relationships supported by genetic evidences. GePhEx is primarily based on the thorough analysis of linkage disequilibrium between disease-associated variants and also considers relationships based on genes, pathways or drug-targets, leveraging on publicly available variant-disease associations to detect potential relationships between diseases. We demonstrate that GePhEx does retrieve well-known relationships as well as novel ones, and that, thus, it might help shedding light on the patho-physiological mechanisms underlying complex diseases. To this end, we investigate the potential relationship between schizophrenia and lung cancer, first detected using GePhEx and provide further evidence supporting a functional link between them.

Published
2020

19. A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells

Author

European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Gil-Varea, Elia, Fedetz, María, Eixarch, Herena, Spataro, Nino, Villar, Luisa María, Urcelay, Elena, Sáiz, Albert, Fernández, Óscar, Leyva, Laura, Ramió-Torrentà, Lluís, Vandenbroeck, Koen, Otaegui, David, Castillo-Triviño, Tamara, Izquierdo, Guillermo, Malhotra, Sunny, Bosch, Elena, Navarro, Arcadi, Alcina, Antonio, Montalbán, Xavier, Matesanz, F., Comabella, Manuel, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Ministerio de Economía y Competitividad (España), Gil-Varea, Elia, Fedetz, María, Eixarch, Herena, Spataro, Nino, Villar, Luisa María, Urcelay, Elena, Sáiz, Albert, Fernández, Óscar, Leyva, Laura, Ramió-Torrentà, Lluís, Vandenbroeck, Koen, Otaegui, David, Castillo-Triviño, Tamara, Izquierdo, Guillermo, Malhotra, Sunny, Bosch, Elena, Navarro, Arcadi, Alcina, Antonio, Montalbán, Xavier, Matesanz, F., and Comabella, Manuel

Abstract

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.

Published
2020

20. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, primary, Cousin, Margot A., additional, Challman, Thomas D., additional, Wain, Karen E., additional, Powis, Zöe, additional, Minks, Kelly, additional, Trimouille, Aurélien, additional, Lasseaux, Eulalie, additional, Lacombre, Didier, additional, Angelini, Chloé, additional, Michaud, Vincent, additional, Van-Gils, Julien, additional, Spataro, Nino, additional, Ruiz, Anna, additional, Gabau, Elizabeth, additional, Stolerman, Elliot, additional, Washington, Camerun, additional, Louie, Raymond J., additional, Lanpher, Brendan C, additional, Kemppainen, Jennifer L., additional, Innes, A. Micheil, additional, Kooy, R. Frank, additional, Meuwissen, Marije, additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Vera, Gabriella, additional, Diderich, Karin E M, additional, Sheidley, Beth Rosen, additional, El Achkar, Christelle Moufawad, additional, Park, Meredith, additional, Hamdan, Fadi F., additional, Michaud, Jacques L., additional, Lewis, Ann J., additional, Zweier, Christiane, additional, Reis, André, additional, Wagner, Matias, additional, Weigand, Heike, additional, Journel, Hubert, additional, Keren, Boris, additional, Passemard, Sandrine, additional, Mignot, Cyril, additional, van Gassen, Koen L.I., additional, Brilstra, Eva H., additional, Itzikowitz, Gina, additional, O’Heir, Emily, additional, Allen, Jake, additional, Donald, Kirsten A., additional, Korf, Bruce R., additional, Skelton, Tammi, additional, Thompson, Michelle L, additional, Robin, Nathaniel H., additional, Rudy, Natasha, additional, Dobyns, William B., additional, Foss, Kimberly, additional, Zarate, Yuri A, additional, Bosanko, Katherine A., additional, Alembik, Yves, additional, Durand, Benjamin, additional, Mau-Them, Frédéric Tran, additional, Ranza, Emmanuelle, additional, Blanc, Xavier, additional, Antonarakis, Stylianos E., additional, McWalter, Kirsty, additional, Torti, Erin, additional, Millan, Francisca, additional, Dameron, Amy, additional, Tokita, Mari J., additional, Zimmermann, Michael T., additional, Dsouza, Nikita R., additional, Klee, Eric W., additional, Piton, Amélie, additional, and Gerard, Bénédicte, additional

Published
2020
Full Text
View/download PDF

21. FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

Author

Schneider, Amy L., primary, Myers, Candace T., additional, Muir, Alison M., additional, Calvert, Sophie, additional, Basinger, Alice, additional, Perry, M. Scott, additional, Rodan, Lance, additional, Helbig, Katherine L., additional, Chambers, Chelsea, additional, Gorman, Kathleen M., additional, King, Mary D., additional, Donkervoort, Sandra, additional, Soldatos, Ariane, additional, Bönnemann, Carsten G., additional, Spataro, Nino, additional, Gabau, Elisabeth, additional, Arellano, Montserrat, additional, Cappuccio, Gerarda, additional, Brunetti‐Pierri, Nicola, additional, Rossignol, Elsa, additional, Hamdan, Fadi F., additional, Michaud, Jacques L., additional, Balak, Christopher, additional, Mefford, Heather C., additional, and Scheffer, Ingrid E., additional

Published
2020
Full Text
View/download PDF

23. New genes involved in Angelman syndrome-like: expanding the genetic spectrum

Author

Aguilera, Cinthia, primary, Gabau, Elisabeth, additional, Ramirez-Mallafré, Ariadna, additional, Brun-Gasca, Carme, additional, Dominguez-Carral, Jana, additional, Delgadillo, Veronica, additional, Laurie, Steve, additional, Derdak, Sophia, additional, Padilla, Natàlia, additional, de la Cruz, Xavier, additional, Capdevila, Núria, additional, Spataro, Nino, additional, Baena, Neus, additional, Guitart, Miriam, additional, and Ruiz, Anna, additional

Published
2020
Full Text
View/download PDF

24. Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes

Author

Gil‐Varea, Elia, primary, Spataro, Nino, additional, Villar, Luisa María, additional, Tejeda‐Velarde, Amalia, additional, Midaglia, Luciana, additional, Matesanz, Fuencisla, additional, Malhotra, Sunny, additional, Eixarch, Herena, additional, Patsopoulos, Nikolaos, additional, Fernández, Óscar, additional, Oliver‐Martos, Begoña, additional, Saiz, Albert, additional, Llufriu, Sara, additional, Ramió‐Torrentà, Lluís, additional, Quintana, Ester, additional, Izquierdo, Guillermo, additional, Alcina, Antonio, additional, Bosch, Elena, additional, Navarro, Arcadi, additional, Montalban, Xavier, additional, and Comabella, Manuel, additional

Published
2020
Full Text
View/download PDF

25. A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells

Author

Gil-Varea, Elia, primary, Fedetz, Maria, additional, Eixarch, Herena, additional, Spataro, Nino, additional, Villar, Luisa María, additional, Urcelay, Elena, additional, Saiz, Albert, additional, Fernández, Óscar, additional, Leyva, Laura, additional, Ramió-Torrentà, Lluís, additional, Vandenbroeck, Koen, additional, Otaegui, David, additional, Castillo-Triviño, Tamara, additional, Izquierdo, Guillermo, additional, Malhotra, Sunny, additional, Bosch, Elena, additional, Navarro, Arcadi, additional, Alcina, Antonio, additional, Montalban, Xavier, additional, Matesanz, Fuencisla, additional, and Comabella, Manuel, additional

Published
2020
Full Text
View/download PDF

26. MSJ851428_supplementary_material – Supplemental material for A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis

Author

Peroni, Silvia, Sorosina, Melissa, Malhotra, Sunny, Clarelli, Ferdinando, Osiceanu, Ana Maria, Ferrè, Laura, Roostaei, Tina, Rio, Jordi, Midaglia, Luciana, Villar, Luisa María, Álvarez-Cermeño, José Carlos, Guaschino, Clara, Radaelli, Marta, Citterio, Lorena, Lechner-Scott, Jeannette, Spataro, Nino, Arcadi Navarro, Martinelli, Vittorio, Montalban, Xavier, Weiner, Howard L, Jager, Philip De, Comi, Giancarlo, Esposito, Federica, Comabella, Manuel, and Martinelli-Boneschi, Filippo

Subjects
FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 110904 Neurology and Neuromuscular Diseases
Abstract

Supplemental material, MSJ851428_supplementary_material for A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis by Silvia Peroni, Melissa Sorosina, Sunny Malhotra, Ferdinando Clarelli, Ana Maria Osiceanu, Laura Ferrè, Tina Roostaei, Jordi Rio, Luciana Midaglia, Luisa María Villar, José Carlos Álvarez-Cermeño, Clara Guaschino, Marta Radaelli, Lorena Citterio, Jeannette Lechner-Scott, Nino Spataro, Arcadi Navarro, Vittorio Martinelli, Xavier Montalban, Howard L Weiner, Philip de Jager, Giancarlo Comi, Federica Esposito, Manuel Comabella and Filippo Martinelli-Boneschi in Multiple Sclerosis Journal

Published
2019
Full Text
View/download PDF

27. Reply to: Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Rodríguez, Juan Antonio, Farré, Xavier, Muntané, Gerard, Marigorta, Urko M., Hughes, David A., Spataro, Nino, Bosch, Elena, Navarro, Arcadi, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Rodríguez, Juan Antonio, Farré, Xavier, Muntané, Gerard, Marigorta, Urko M., Hughes, David A., Spataro, Nino, Bosch, Elena, and Navarro, Arcadi

Abstract

Long and Zhang1 present empirical and conceptual objections to our results2. Concerning data, they observe that a single disease provides nearly all the support for mutation accumulation (MA). On a more theoretical note, they find no evidence for a putative prediction of antagonistic pleiotropy (AP): that at ‘each’ antagonistic pleiotropic single nucleotide polymorphism (SNP), the risk allele frequencies (RAFs) should be lower for early-onset rather than late-onset diseases.

Published
2019

30. A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis

Author

Peroni, Silvia, primary, Sorosina, Melissa, additional, Malhotra, Sunny, additional, Clarelli, Ferdinando, additional, Osiceanu, Ana Maria, additional, Ferrè, Laura, additional, Roostaei, Tina, additional, Rio, Jordi, additional, Midaglia, Luciana, additional, Villar, Luisa María, additional, Álvarez-Cermeño, José Carlos, additional, Guaschino, Clara, additional, Radaelli, Marta, additional, Citterio, Lorena, additional, Lechner-Scott, Jeannette, additional, Spataro, Nino, additional, Navarro, Arcadi, additional, Martinelli, Vittorio, additional, Montalban, Xavier, additional, Weiner, Howard L, additional, de Jager, Philip, additional, Comi, Giancarlo, additional, Esposito, Federica, additional, Comabella, Manuel, additional, and Martinelli-Boneschi, Filippo, additional

Published
2019
Full Text
View/download PDF

31. De novocoding variants in the AGO1gene cause a neurodevelopmental disorder with intellectual disability

Author

Schalk, Audrey, Cousin, Margot A, Dsouza, Nikita R, Challman, Thomas D, Wain, Karen E, Powis, Zoe, Minks, Kelly, Trimouille, Aurélien, Lasseaux, Eulalie, Lacombe, Didier, Angelini, Chloé, Michaud, Vincent, Van-Gils, Julien, Spataro, Nino, Ruiz, Anna, Gabau, Elizabeth, Stolerman, Elliot, Washington, Camerun, Louie, Ray, Lanpher, Brendan C, Kemppainen, Jennifer L, Innes, Micheil, Kooy, Frank, Meuwissen, Marije, Goldenberg, Alice, Lecoquierre, Francois, Vera, Gabriella, Diderich, Karin E M, Sheidley, Beth, El Achkar, Christelle Moufawad, Park, Meredith, Hamdan, Fadi F, Michaud, Jacques L, Lewis, Ann J, Zweier, Christiane, Reis, André, Wagner, Matias, Weigand, Heike, Journel, Hubert, Keren, Boris, Passemard, Sandrine, Mignot, Cyril, van Gassen, Koen, Brilstra, Eva H, Itzikowitz, Gina, O'Heir, Emily, Allen, Jake, Donald, Kirsten A, Korf, Bruce Richard, Skelton, Tammi, Thompson, Michelle, Robin, Nathaniel H, Rudy, Natasha L, Dobyns, William B, Foss, Kimberly, Zarate, Yuri Alexander, Bosanko, Katherine A, Alembik, Yves, Durand, Benjamin, Tran Mau-them, Frederic, Ranza, Emmanuelle, Blanc, Xavier, Antonarakis, Stylianos E, McWalter, Kirsty, Torti, Erin, Millan, Francisca, Dameron, Amy, Tokita, Mari, Zimmermann, Michael T, Klee, Eric W, Piton, Amelie, and Gerard, Benedicte

Abstract

BackgroundHigh-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).MethodsThis study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1coding variants, occurring de novo for all those whose transmission could have been verified (26/28).ResultsA total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.ConclusionOur study establishes that de novo coding variants in AGO1are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

Published
2022
Full Text
View/download PDF

32. Functional relevance for CXCR5 variants associated with multiple sclerosis

Author

Gil-Varea, Elia, Fedetz, María, Spataro, Nino, Fernández, Óscar, Sáiz, Albert, Ramió-Torrentà, Lluís, Izquierdo, Guillermo, Malhotra, Sunny, Navarro, Arcadi, Bosch, Elena, Alcina, Antonio, Montalbán, Xavier, Matesanz, F., Comabella, Manuel, Gil-Varea, Elia, Fedetz, María, Spataro, Nino, Fernández, Óscar, Sáiz, Albert, Ramió-Torrentà, Lluís, Izquierdo, Guillermo, Malhotra, Sunny, Navarro, Arcadi, Bosch, Elena, Alcina, Antonio, Montalbán, Xavier, Matesanz, F., and Comabella, Manuel

Published
2018

33. The MS risk variant rs2762943 of the CYP24A1 gene is associated with decreased serum levels of the active form of vitamin D

Author

Gil-Varea, Elia, Matesanz, F., Ferrer, R., Spataro, Nino, Fernández, O., Sáiz, Albert, Ramió-Torrentà, Lluís, Izquierdo, Guillermo, Malhotra, Sunny, Navarro, Arcadi, Bosch, Elena, Alcina, Antonio, Montalbán, Xavier, Comabella, Manuel, Gil-Varea, Elia, Matesanz, F., Ferrer, R., Spataro, Nino, Fernández, O., Sáiz, Albert, Ramió-Torrentà, Lluís, Izquierdo, Guillermo, Malhotra, Sunny, Navarro, Arcadi, Bosch, Elena, Alcina, Antonio, Montalbán, Xavier, and Comabella, Manuel

Published
2018

34. FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability.

Author

Schneider, Amy L., Myers, Candace T., Muir, Alison M., Calvert, Sophie, Basinger, Alice, Perry, M. Scott, Rodan, Lance, Helbig, Katherine L., Chambers, Chelsea, Gorman, Kathleen M., King, Mary D., Donkervoort, Sandra, Soldatos, Ariane, Bönnemann, Carsten G., Spataro, Nino, Gabau, Elisabeth, Arellano, Montserrat, Cappuccio, Gerarda, Brunetti‐Pierri, Nicola, and Rossignol, Elsa

Subjects
INTELLECTUAL disabilities, CHILDREN with epilepsy, MOVEMENT disorders, LENNOX-Gastaut syndrome, INFANTILE spasms, 22Q11 deletion syndrome, AGE of onset, PEOPLE with epilepsy
Abstract

Chromosome 1q41‐q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41‐q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41‐q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41‐q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41‐q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug‐resistant epilepsy, and hyperkinetic movement disorders. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

35. A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis.

Author

Peroni, Silvia, Sorosina, Melissa, Malhotra, Sunny, Clarelli, Ferdinando, Osiceanu, Ana Maria, Ferrè, Laura, Roostaei, Tina, Rio, Jordi, Midaglia, Luciana, Villar, Luisa María, Álvarez-Cermeño, José Carlos, Guaschino, Clara, Radaelli, Marta, Citterio, Lorena, Lechner-Scott, Jeannette, Spataro, Nino, Navarro, Arcadi, Martinelli, Vittorio, Montalban, Xavier, and Weiner, Howard L

Subjects
MULTIPLE sclerosis, ENDOTHELIAL cells, GENE expression, SURVIVAL analysis (Biometry), GENETIC polymorphisms, VENOUS pressure
Abstract

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients. Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. Methods: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. Results: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10−4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10−6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. Conclusions: Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

36. Genome-phenome explorer (GePhEx): a tool for the visualization and interpretation of phenotypic relationships supported by genetic evidence.

Author

Farré, Xavier, Spataro, Nino, Haziza, Frederic, Rambla, Jordi, and Navarro, Arcadi

Subjects
*PHENOTYPES, *LUNG cancer, *SCHIZOPHRENIA, *LINKAGE disequilibrium, *DATA mining
Abstract

Motivation Association studies based on SNP arrays and Next Generation Sequencing technologies have enabled the discovery of thousands of genetic loci related to human diseases. Nevertheless, their biological interpretation is still elusive, and their medical applications limited. Recently, various tools have been developed to help bridging the gap between genomes and phenomes. To our knowledge, however none of these tools allows users to retrieve the phenotype-wide list of genetic variants that may be linked to a given disease or to visually explore the joint genetic architecture of different pathologies. Results We present the Genome-Phenome Explorer (GePhEx), a web-tool easing the visual exploration of phenotypic relationships supported by genetic evidences. GePhEx is primarily based on the thorough analysis of linkage disequilibrium between disease-associated variants and also considers relationships based on genes, pathways or drug-targets, leveraging on publicly available variant-disease associations to detect potential relationships between diseases. We demonstrate that GePhEx does retrieve well-known relationships as well as novel ones, and that, thus, it might help shedding light on the patho-physiological mechanisms underlying complex diseases. To this end, we investigate the potential relationship between schizophrenia and lung cancer, first detected using GePhEx and provide further evidence supporting a functional link between them. Availability and implementation GePhEx is available at: https://gephex.ega-archive.org/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

37. Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

Author

Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Spataro, Nino, Roca-Umbert, Ana, Valles, Mònica, Bosch, Elena, Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, Spataro, Nino, Roca-Umbert, Ana, Valles, Mònica, and Bosch, Elena

Abstract

[Background] The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases., [Methods] Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR., [Results] We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases., [Conclusions] Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2017

38. Human genetic disorders: Mendelian and complex diseases

Author

Spataro, Nino, 1984, Bosch Fusté, Elena, and Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut

Subjects
Mendelian disorders, Parkinson's disease, Malaltia de Parkinson, Mètodes de col.lapse, Copy number variation (CNVs), Collapsing methods, Malalties mendelianes, Complex diseases, Malalties complexes, Variació en el número de còpies
Abstract

From Darwin’s “On the Origin of Species”, many years elapsed before human diseases were considered in an evolutionary framework. Besides theoretical and empirical advances, we are far from the complete understanding of disease aetiology. Highly penetrant disorders with Mendelian inheritance are mostly explained by the mutation-selection balance model, which is insufficient to describe the selective pressures acting on the full set of alleles related to diseases. We show in the first two papers that Next Generation Sequencing (NGS) technologies provide a unique opportunity to investigate variation and contribute to the understanding of the genetic architecture of disease. Besides exploring the role of rare and copy number variants in Parkinson’s disease (PD), we demonstrate the functional relation between Mendelian and idiopathic PD. In the last paper, we report that variation in genes previously related to Mendelian disorders has a more important role in driving complex disease susceptibility than genes associated only to complex diseases., Des de l'Origen de les Espècies de Darwin van passar molts anys abans que les malalties humanes fossin considerades sota un marc evolutiu. Tanmateix, tot i els darrers avenços teòrics i empírics, estem molt lluny de tenir una comprensió completa de l'etiologia de les malalties humanes. Mentre els trastorns altament penetrants amb herència mendeliana poden explicar-se sota un model d’equilibri mutació-selecció, aquest és insuficient per descriure les pressions selectives que actuen sobre tot el conjunt d'al·lels associats a malalties. Mostrem en els dos primers treballs que les noves tecnologies de seqüenciació proporcionen una oportunitat única per investigar la variació i contribuir a la comprensió de l'arquitectura genètica de la malaltia. A més d'explorar el paper de les variants rares i en el nombre de còpies en la malaltia de Parkinson (PD), demostrem la relació funcional entre les formes mendelianes i idiopàtiques d’aquesta malaltia. En el darrer treball, mostrem sota una perspectiva evolutiva i funcional que, en comparació amb la variació genètica en gens associats només a malalties complexes, la variació en gens prèviament relacionats amb trastorns Mendelians sembla tenir un paper clarament més important en la susceptibilitat a la malaltia complexa.

Published
2016

39. Signatures of human adaptation in quantitative trait loci influencing micronutrient homeostasis in liver

Author

Engelken, Johannes, Scherr, Anna-Lena, Jiménez-Álvarez, Victoria, Codina-Solà, Marta, Medina-Stacey, Daniel, Spataro, Nino, Calafell, Francesc, and Bosch, Elena

Abstract

Engelken, Johannes.-- Trabajo presentado en el V Congreso de la Sociedad Española de Biología Evolutiva (SESBE 2016), celebrado en Murcia del 18 al 21 de enero de 2016., Micronutrients possess vital functions at molecular, cellular and physiological levels, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 human liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 SNPs in the same sample set. We detected significant associations between SNP genotypes and eight protein abundances (pQTLs), 10 mRNA levels (eQTLs) and 15 micronutrient concentrations (nutriQTLs). Six of these survived the false discovery rate (FDR) cutoff: i) one pQTL for GPX2 (rs10133290); ii) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and iii) three nutriQTLs: the pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1 GPX3, SLC30A9 and SLC39A8, which are related to zinc and selenium. Overall, this multilayered, integrative study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients.

Published
2016

40. Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

Author

Spataro, Nino, Roca-Umbert, Ana, Cervera Carles, Laura, Vallès, Mònica, Anglada, Roger, Pagonabarraga, Javier, Pascual-Sedano, Berta, Campolongo, Antonia, Kulisevsky, Jaime, Casals, Ferran, Clarimón, Jordi, Bosch, Elena, and Universitat Autònoma de Barcelona

Subjects
Parkinson's disease, Next generation sequencing, Structural variants, XHMM software
Abstract

The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases. Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR. We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases. Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2016

41. NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients

Author

Malhotra, Sunny, primary, Sorosina, Melissa, additional, Río, Jordi, additional, Peroni, Silvia, additional, Midaglia, Luciana, additional, Villar, Luisa M, additional, Álvarez-Cermeño, José C, additional, Schroeder, Ina, additional, Esposito, Federica, additional, Clarelli, Ferdinando, additional, Zettl, Uwe K, additional, Lechner-Scott, Jeannette, additional, Spataro, Nino, additional, Navarro, Arcadi, additional, Comi, Giancarlo, additional, Montalban, Xavier, additional, Martinelli-Boneschi, Filippo, additional, and Comabella, Manuel, additional

Published
2017
Full Text
View/download PDF

42. Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

Author

Dols-Icardo, Oriol, primary, García-Redondo, Alberto, additional, Rojas-García, Ricardo, additional, Borrego-Hernández, Daniel, additional, Illán-Gala, Ignacio, additional, Muñoz-Blanco, José Luís, additional, Rábano, Alberto, additional, Cervera-Carles, Laura, additional, Juárez-Rufián, Alexandra, additional, Spataro, Nino, additional, De Luna, Noemí, additional, Galán, Lucía, additional, Cortes-Vicente, Elena, additional, Fortea, Juan, additional, Blesa, Rafael, additional, Grau-Rivera, Oriol, additional, Lleó, Alberto, additional, Esteban-Pérez, Jesús, additional, Gelpi, Ellen, additional, and Clarimón, Jordi, additional

Published
2017
Full Text
View/download PDF

44. Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver

Author

Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Volkswagen Foundation, Engelken, Johannes, Scherr, Anna-Lena, Jiménez-Álvarez, Victoria, Codina-Solà, Marta, Medina-Stacey, Daniel, Spataro, Nino, Calafell, Francesc, Bosch, Elena, Ministerio de Ciencia e Innovación (España), Generalitat de Catalunya, Instituto de Salud Carlos III, Volkswagen Foundation, Engelken, Johannes, Scherr, Anna-Lena, Jiménez-Álvarez, Victoria, Codina-Solà, Marta, Medina-Stacey, Daniel, Spataro, Nino, Calafell, Francesc, and Bosch, Elena

Abstract

Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients.

Published
2016

45. Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients

Author

Spataro, Nino, primary, Roca‐Umbert, Ana, additional, Cervera‐Carles, Laura, additional, Vallès, Mònica, additional, Anglada, Roger, additional, Pagonabarraga, Javier, additional, Pascual‐Sedano, Berta, additional, Campolongo, Antònia, additional, Kulisevsky, Jaime, additional, Casals, Ferran, additional, Clarimón, Jordi, additional, and Bosch, Elena, additional

Published
2016
Full Text
View/download PDF

46. Disease genes and evolution: a complex issue

Author

Spataro, Nino, Rodríguez-Pérez, Juan Antonio, Navarro, Arcadi, and Bosch, Elena

Abstract

Trabajo presentado en la 4th Meeting of the Spanish Society of the Evolutionary Biology (SESBE 2013) celebrada en Barcelona del 27 al 29 de noviembre de 2013.

Published
2013

47. NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients.

Author

Malhotra, Sunny, Sorosina, Melissa, Río, Jordi, Peroni, Silvia, Midaglia, Luciana, Villar, Luisa M., Álvarez-Cermeño, José C., Schroeder, Ina, Esposito, Federica, Clarelli, Ferdinando, Zettl, Uwe K., Lechner-Scott, Jeannette, Spataro, Nino, Navarro, Arcadi, Comi, Giancarlo, Montalban, Xavier, Martinelli-Boneschi, Filippo, and Comabella, Manuel

Subjects
GENETIC polymorphisms, INTERFERON beta 1b, GENETICS of multiple sclerosis, MYELIN sheath diseases, GENOTYPES
Abstract

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

48. Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the expansion mutation.

Author

Dols-Icardo, Oriol, García-Redondo, Alberto, Rojas-García, Ricardo, Borrego-Hernández, Daniel, Illán-Gala, Ignacio, Muñoz-Blanco, José Luís, Rábano, Alberto, Cervera-Carles, Laura, Juárez-Rufán, Alexandra, Spataro, Nino, De Luna, Noemí, Galán, Lucía, Cortes-Vicente, Elena, Fortea, Juan, Blesa, Rafael, Grau-Rivera, Oriol, Lleó, Alberto, Esteban-Pérez, Jesús, Gelpi, Ellen, and Clarimón, Jordi

Subjects
GENETICS of amyotrophic lateral sclerosis, FRONTOTEMPORAL dementia, GENETIC mutation, MOTOR neurons, NUCLEOTIDE sequencing, EXOMES, GENETICS
Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum.Objectives: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases.Methods: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes.Results: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4.Conclusion: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

49. Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver

Author

Engelken, Johannes, primary, Espadas, Guadalupe, additional, Mancuso, Francesco M., additional, Bonet, Nuria, additional, Scherr, Anna-Lena, additional, Jímenez-Álvarez, Victoria, additional, Codina-Solà, Marta, additional, Medina-Stacey, Daniel, additional, Spataro, Nino, additional, Stoneking, Mark, additional, Calafell, Francesc, additional, Sabidó, Eduard, additional, and Bosch, Elena, additional

Published
2015
Full Text
View/download PDF

50. Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients.

Author

Spataro, Nino, Roca‐Umbert, Ana, Cervera‐Carles, Laura, Vallès, Mònica, Anglada, Roger, Pagonabarraga, Javier, Pascual‐Sedano, Berta, Campolongo, Antònia, Kulisevsky, Jaime, Casals, Ferran, Clarimón, Jordi, and Bosch, Elena

Subjects
*GENETICS, *LONGITUDINAL method, *PARKINSON'S disease, *SEQUENCE analysis
Abstract

Background: The analysis of coverage depth in next-generation sequencing data allows the detection of gene dose alterations. We explore the frequency of such structural events in a Spanish cohort of sporadic PD cases.Methods: Gene dose alterations were detected with the eXome-Hidden Markov Model (XHMM) software from depth of coverage in resequencing data available for 38 Mendelian and other risk PD loci in 394 individuals (249 cases and 145 controls) and subsequently validated by quantitative PCR.Results: We identified 10 PD patients with exon dosage alterations in PARK2, GBA-GBAP1, and DJ1. Additional functional variants, including 2 novel nonsense mutations (p.Arg1552Ter in LRRK2 and p.Trp90Ter in PINK1), were confirmed by Sanger sequencing. This combined approach disclosed the genetic cause of 12 PD cases.Conclusions: Gene dose alterations related to PD can be correctly identified from targeting resequencing data. This approach substantially improves the detection rate of cases with causal genetic alterations. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results