Browsing by Author "Mouga, Susana"
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- Characterization and expression analysis of a CNV at chromosome 10q22 encompassing 14 genes in an autistic patientPublication . C. Conceição, Inês; Correia, Catarina; Oliveira, Bárbara; Duque, Frederico; Mouga, Susana; Oliveira, Guiomar; M. Vicente, AstridAutism Spectrum Disorders (ASD) have a strong genetic component, with an estimated heritability of over 90%. Recent studies carried out by the Autism Genome Project (AGP) consortium suggest that rare Copy Number Variants (CNV), characterized by submicroscopic chromosomal deletions and duplications, are more frequent in ASD compared to controls, and may play an important role in susceptibility to this disorder. However, to adequately assess pathogenicity, a detailed characterization of patients CNVs is required. We have been characterizing potentially pathogenic rare CNVs identified by the AGP whole genome CNV analysis of 1,275 ASD individuals. CNV validation in patients and parents and characterization were performed by qPCR and Long-range PCR. One autistic patient showed a rare deletion absent in 4964 controls of European ancestry with no psychiatric disease history. This deletion was located at 10q22, and encompassed 14 genes, including ANXA7, ZMYND17, PPP3CB and CAMK2G. We validated this CNV as de novo, and accurate breakpoint determination showed that it is smaller than predicted by CNV identification algorithms, including only part of CAMK2G. We found that a 39 nucleotide addition occurred with the deletion, a mutational mechanism previously observed in other CNVs. Expression analysis of ANXA7, ZMYND17 and PPP3CB in this patient, in comparison with controls, is ongoing. Previous studies identified a genetic association of the ANXA7, PPP3CB and ZMYND17 region with schizophrenia, and significant expression alterations in schizophrenic patients. ANXA7 encodes Annexin7, involved in membrane fusion; interestingly, CNVs in other Annexin genes (ANXA1) have been found in ASD. PPP3CB plays an important role in synaptic plasticity, learning and memory. ZMYND17 has no known function. Our results suggest that alterations in these genes may be risk factors co-observed in autism and schizophrenia. Additional genetic and functional studies may lead to a better understanding of the common pathways between these neuropsychiatric disorders.
- CNV Characterization, Inheritance and Phenotypic Correlations in Families With AutismPublication . C. Conceição, Inês; Correia, Catarina; Oliveira, Bárbara; M. Rama, Maria; Café, Cátia; Almeida, Joana; Mouga, Susana; Duque, Frederico; Oliveira, Guiomar; M. Vicente, AstridAutism Spectrum Disorders (ASD) have a strong genetic component, with an estimated heritability of over 90%1. Recent studies carried out by the Autism Genome Project (AGP) consortium suggest that rare Copy Number Variants (CNVs), characterized by submicroscopic chromosomal deletions and duplications, are more frequent in ASD compared to controls, and may play an important role in susceptibility to this disorder2. However, to adequately assess pathogenicity, a detailed characterization of patients CNVs and phenotype is required. The goal of this study was to establish the clinical and etiological relevance for ASD of potentially pathogenic CNVs identified in a Portuguese population sample by whole genome CNV analysis, through the detailed characterization of CNVs and correlation with clinical phenotypes. Analysis of the AGP genome-wide CNV results using 1M SNP microarray2 identified a total of 14218 CNVs in 342 Portuguese probands. We selected 291 CNVs, present in 191 individuals (19 females and 172 males), using the following criteria: 1) CNVs that contained implicated/candidate genes for ASD; 2) CNVs in genomic regions known to be implicated/candidate for ASD; 3) CNVs in regions associated with syndromes with ASD symptoms; and 4) high confidence CNVs that did not overlap more than 20% with controls in available databases. We explored recurrence rates, genic content, regulatory elements, inheritance patterns and phenotypic correlations.
- Neurometabolic profiles of autism spectrum disorder patients with genetic variants in specific neurotransmission and synaptic genesPublication . Vilela, Joana; Pereira, Andreia C.; Violante, Inês R.; Mouga, Susana; Rasga, Célia; Santos, João Xavier; Martiniano, Hugo; Marques, Ana Rita; Oliveira, Guiomar; Castelo-Branco, Miguel; Vicente, Astrid MouraAutism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, and restricted and repetitive patterns of behavior. ASD presents as a clinical spectrum, with variable levels of severity and multiple co-occurring conditions. The etiology of ASD may involve hundreds of genes and there is evidence that neurotransmitter and synaptic (NS) pathways are implicated. Proton Magnetic Resonance Spectroscopy (H-MRS) has made it possible to study the concentration of brain neurometabolites and compare their levels in the brains of ASD and control individuals. We integrated genetic variants in NS genes with H-MRS analysis, and identified 12 predicted damaging variants (PDVs) in 12 NS genes in 10 ASD individuals, most mapping to genes involved in Gamma-aminobutyric acid (GABA) and glutamate pathways. Total creatine (tCr) and total N-acetyl aspartate (tNAA), markers of bioenergetics and neuronal metabolism, respectively, were lower in ASD patients with genetic alterations in NS genes compared to a control group without ASD. We conclude that PDVs in NS genes that are important for the regulation of glutamate or involved in GABAergic functions are associated with neurometabolic alterations, and that dysfunction in glutamatergic and/or GABAergic pathways may be implicated as these pathways are linked to the metabolic measures altered in cases.
- Phenotypic categorization of putative pathogenic CNVs in a population of Autism Spectrum Disorder patientsPublication . Conceição, Inês C.; Correia, Catarina; Oliveira, Bárbara; Rama, Maria M.; Café, Cátia; Almeida, Joana; Mouga, Susana; Duque, Frederico; Oliveira, Guiomar; Vicente, A.M.
- Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disordersPublication . Weiner, Daniel J.; Wigdor, Emilie M.; Ripke, Stephan; Walters, Raymond K.; Kosmicki, Jack A.; Grove, Jakob; Samocha, Kaitlin E.; Goldstein, Jacqueline I.; Okbay, Aysu; Bybjerg-Grauholm, Jonas; Werge, Thomas; Minshew, Nancy; Merikangas, Alison; McMahon, William M.; McGrew, Susan G.; Ladd-Acosta, Christine; Mattheisen, Manuel; Hougaard, David M.; Jacob, Suma; Bishop, Somer; Iliadou, Bozenna; Arking, Dan E.; Hultman, Christina M.; Hertz-Picciotto, Irva; Hendren, Robert; Hansen, Christine S.; Haines, Jonathan L.; Guter, Stephen J.; Grice, Dorothy E.; Green, Jonathan M.; Taylor, Jacob; Mortensen, Preben Bo; Skuse, David; Green, Andrew; Goldberg, Arthur P.; Gillberg, Christopher; Gilbert, John; Gallagher, Louise; Freitag, Christine M.; Fombonne, Eric; Folstein, Susan E.; Fernandez, Bridget; Fallin, M Daniele; Devlin, Bernie; Børglum, Anders D.; Bækvad-Hansen, Marie; Ercan-Sencicek, A Gulhan; Ennis, Sean; Duque, Frederico; Duketis, Eftichia; Delorme, Richard; De Rubeis, Silvia; De Jonge, Maretha V.; Dawson, Geraldine; Anney, Richard; Cuccaro, Michael L.; Smith, George Davey; Correia, Catarina T.; Dumont, Ashley; Conroy, Judith; Conceição, Inês C.; Chiocchetti, Andreas G.; Celestino-Soper, Patrícia B.S.; Casey, Jillian; Cantor, Rita M.; Mattheisen, Manuel; Café, Cátia; Brennan, Sean; Daly, Mark J.; Bourgeron, Thomas; Bolton, Patrick F.; Hansen, Christine; Bölte, Sven; Bolshakova, Nadia; Betancur, Catalina; Bernier, Raphael; Sanders, Stephan J.; Beaudet, Arthur L.; Battaglia, Agatino; Bal, Vanessa H.; Robinson, Elise B.; Baird, Gillian; Bailey, Anthony J.; Bækvad-Hansen, Marie; Hansen, Thomas F.; Bader, Joel S.; Bacchelli, Elena; Nordentoft, Merete; Anagnostou, Evdokia; Amaral, David; Almeida, Joana; Buxbaum, Joseph D.; Moran, Jennifer; Chakravarti, Aravinda; Cook, Edwin H.; Coon, Hilary; Geschwind, Daniel H.; Howrigan, Daniel; Nørgaard-Pedersen, Bent; Gill, Michael; Hakonarson, Hakon; Hallmayer, Joachim; Palotie, Aarno; Santangelo, Susan; Mors, Ole; Sutcliffe, James S.; Lowe, Jennifer K.; Poterba, Timothy; Martsenkovsky, Igor; Poulsen, Jesper; Stevens, Christine; Anttila, Verneri; Holmans, Peter; Huang, Hailiang; Klei, Lambertus; Lee, Phil H; Medland, Sarah E.; Neale, Benjamin; Lord, Catherine; Martin, Donna M.; Weiss, Lauren A.; Zwaigenbaum, Lonnie; Yu, Timothy W.; Wittemeyer, Kerstin; Willsey, A Jeremy; Wijsman, Ellen M; Wassink, Thomas H.; Waltes, Regina; Walsh, Christopher A.; Wallace, Simon; Mane, Shrikant M.; Levitt, Pat; Vorstman, Jacob A.S.; Vieland, Veronica J.; Vicente, Astrid M.; van Engeland, Herman; Tsang, Kathryn; Thompson, Ann P.; Szatmari, Peter; Svantesson, Oscar; Steinberg, Stacy; Magnusson, Pall; Stefansson, Kari; Martin, Christa Lese; Stefansson, Hreinn; State, Matthew W.; Soorya, Latha; Silagadze, Teimuraz; Scherer, Stephen W.; Schellenberg, Gerard D.; Sandin, Sven; Saemundsen, Evald; Magalhaes, Tiago; Rouleau, Guy A.; Rogé, Bernadette; Ledbetter, David H.; Roeder, Kathryn; Roberts, Wendy; Reichert, Jennifer; Reichenberg, Abraham; Rehnström, Karola; Regan, Regina; Poustka, Fritz; Maestrini, Elena; Poultney, Christopher S.; Piven, Joseph; Pinto, Dalila; Leboyer, Marion; Pericak-Vance, Margaret A.; Pejovic-Milovancevic, Milica; Pedersen, Marianne G.; Pedersen, Carsten B.; Paterson, Andrew D.; Parr, Jeremy R.; Kolevzon, Alexander; Pagnamenta, Alistair T.; Oliveira, Guiomar; Nurnberger, John I.; Nordentoft, Merete; Le Couteur, Ann S.; Murtha, Michael T.; Mouga, Susana; Mors, Ole; Morrow, Eric M.; De Luca, Daniel Moreno; Klauck, Sabine M.; Monaco, Anthony P.Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
- Relevance of Common and Rare CNVs for Autism EtiologyPublication . C. Conceição, Inês; Correia, Catarina; Oliveira, Bárbara; Rama, Maria Margarida; Café, Cátia; Almeida, Joana; Mouga, Susana; Duque, Frederico; Oliveira, Guiomar; M. Vicente, AstridRecent reports by the Autism Genome Project (AGP) consortium and other groups show that Copy Number Variants (CNVs), while individually rare, collectively may explain a large fraction of the etiology of Autism Spectrum Disorders (ASD). The goal of this study was to establish the clinical and etiological relevance for ASD of potentially pathogenic CNVs identified in a Portuguese population sample by whole genome CNV analysis, through the detailed characterization of CNVs and correlation with clinical phenotypes. Analysis of the Autism Genome Project genome-wide CNV results using 1M SNP microarray1 identified a total of 14218 CNVs in 342 Portuguese probands. We selected 292 CNVs, present in 191 individuals (19 females and 172 males), using the following criteria: 1) CNVs that contained implicated/candidate genes for ASD; 2) CNVs in genomic regions known to be implicated/candidate for ASD; 3) CNVs containing genes associated with syndromes with ASD symptoms; and 4) high confidence CNVs that did not overlap more than 20% with controls in available databases. We explored recurrence rates, genic content, regulatory elements, inheritance patterns and clinical correlations