15 results on '"Minopoli, F."'
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2. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders
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State, M., Leblond, C.S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., Konyukh, M., Chaste, P., Ey, E., Rastam, M., Anckarsäter, H., Nygren, G., Gillberg, I.C., Melke, J., Toro, R., Regnault, B., Fauchereau, F., Mercati, O., Lemière, N., Skuse, D., Poot, M., Holt, R., Monaco, A.P., Järvelä, I., Kantojärvi, K., Vanhala, R., Curran, S., Collier, D.A., Bolton, P., Chiocchetti, A., Klauck, S.M., Poustka, F., Freitag, C.M., Waltes, R., Kopp, M., Duketis, E., Bacchelli, E., Minopoli, F., Ruta, L., Battaglia, A., Mazzone, L., Maestrini, E., Sequeira, A.F., Oliveira, B., Vicente, A., Oliveira, G., Pinto, D., Scherer, S.W., Zelenika, D., Delepine, M., Lathrop, M., Bonneau, D., Guinchat, V., Devillard, F., Assouline, B., Mouren, M., Leboyer, M., Gillberg, C., Boeckers, T.M., and Bourgeron, T.
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mental disorders - Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
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- 2012
3. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
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Casey, J.P. Magalhaes, T. Conroy, J.M. Regan, R. Shah, N. Anney, R. Shields, D.C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bolton, P.F. Bourgeron, T. Brennan, S. Cali, P. Correia, C. Corsello, C. Coutanche, M. Dawson, G. De Jonge, M. Delorme, R. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Foley, S. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Green, J. Guter, S.J. Hakonarson, H. Holt, R. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Lamb, J.A. Leboyer, M. Couteur, A.L. Leventhal, B.L. Lord, C. Lund, S.C. Maestrini, E. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Miller, J. Minopoli, F. Mirza, G.K. Munson, J. Nelson, S.F. Nygren, G. Oliveira, G. Pagnamenta, A.T. Papanikolaou, K. Parr, J.R. Parrini, B. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Ragoussis, J. Roge, B. Rutter, M.L. Sequeira, A.F. Soorya, L. Sousa, I. Sykes, N. Stoppioni, V. Tancredi, R. Tauber, M. Thompson, A.P. Thomson, S. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Vorstman, J.A.S. Wallace, S. Wang, K. Wassink, T.H. White, K. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Geschwind, D.H. Haines, J.L. Hallmayer, J. Monaco, A.P. Nurnberger Jr., J.I. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vieland, V.J. Wijsman, E.M. Green, A. Gill, M. Gallagher, L. Vicente, A. Ennis, S.
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mental disorders - Abstract
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. © The Author(s) 2011.
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- 2012
4. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders
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Anney, R.J., Kenny, E.M., O'Dushlaine, C., Parkhomenka, E., Buxbaum, J.D., Sutcliffe, J., Gill, M., Gallagher, L., Bailey, A.J., Fernandez, B.A., Szatmari, P., Nurnberger Jr, J.I., McDougle, C.J., Posey, D.J., Lord, C., Corsello, C., Hus, V., Kolevzon, A., Soorya, L., Parkhomenko, E., Scherer, S.W., Leventhal, B.L., Dawson, G., Vieland, V.J., Hakonarson, H., Glessner, J.T., Kim, C., Wang, K., Schellenberg, G.D., Devlin, B., Klei, L., Patterson, A., Minshew, N., Sutcliffe, J.S., Haines, J.L., Lund, S.C., Thomson, S., Yaspan, B.L., Coon, H., Miller, J., McMahon, W.M., Munson, J., Marshall, C.R., Estes, A., Wijsman, EM., The Autism Genome Project, Pinto, D., Vincent, J.B., Fombonne, E., Betancur, C., Delorme, R., Leboyer, M., Bourgeron, T., Mantoulan, C., Roge, B., Tauber, M., Freitag, C.M., Poustka, F., Duketis, E., Klauck, S.M., Poustka, A., Papanikolaou, K., Tsiantis, J., Anney, R., Bolshakova, N., Brennan, S., Hughes, G., McGrath, J., Merikangas, A., Ennis, S., Green, A., Casey, J.P., Conroy, J.M., Regan, R., Shah, N., Maestrini, E., Bacchelli, E., Minopoli, F., Stoppioni, V., Battaglia, A., Igliozzi, R., Parrini, B., Tancredi, R., Oliveira, G., Almeida, J., Duque, F., Vicente, A.M., Correia, C., Magalhaes, T.R., Gillberg, C., Nygren, G., Jonge, M.D., Van Engeland, H., Vorstman, J.A., Wittemeyer, K., Baird, G., Bolton, P.F, Rutter, M.L., Green, J., Lamb, J.A., Pickles, A., Parr, J.R., Couteur, A.L., Berney, T., McConachie, H., Wallace, S., Coutanche, M., Foley, S., White, K., Monaco, A.P., Holt, R., Farrar, P., Pagnamenta, A.T., Mirza, G.K., Ragoussis, J., Sousa, I., Sykes, N., Wing, K., Hallmayer, J., Cantor, R.M., Nelson, S.F., Geschwind, D.H., Abrahams, B.S., Volkmar, F., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J., Cook, E.H., Guter, S.J., and Jacob, S.
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Pathway analysis ,Autism ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,Gene ontology ,Genome-wide association analysis ,Family-based association test - Abstract
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.
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- 2011
5. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders
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Anney, R.J.L. Kenny, E.M. O'Dushlaine, C. Yaspan, B.L. Parkhomenka, E. Buxbaum, J.D. Sutcliffe, J. Gill, M. Gallagher, L. Bailey, A.J. Fernandez, B.A. Szatmari, P. Scherer, S.W. Patterson, A. Marshall, C.R. Pinto, D. Vincent, J.B. Fombonne, E. Betancur, C. Delorme, R. Leboyer, M. Bourgeron, T. Mantoulan, C. Roge, B. Tauber, M. Freitag, C.M. Poustka, F. Duketis, E. Klauck, S.M. Poustka, A. Papanikolaou, K. Tsiantis, J. Bolshakova, N. Brennan, S. Hughes, G. McGrath, J. Merikangas, A. Ennis, S. Green, A. Casey, J.P. Conroy, J.M. Regan, R. Shah, N. Maestrini, E. Bacchelli, E. Minopoli, F. Stoppioni, V. Battaglia, A. Igliozzi, R. Parrini, B. Tancredi, R. Oliveira, G. Almeida, J. Duque, F. Vicente, A. Correia, C. Magalhaes, T.R. Gillberg, C. Nygren, G. De Jonge, M. Van Engeland, H. Vorstman, J.A.S. Wittemeyer, K. Baird, G. Bolton, P.F. Rutter, M.L. Green, J. Lamb, J.A. Pickles, A. Parr, J.R. Le Couteur, A. Berney, T. McConachie, H. Wallace, S. Coutanche, M. Foley, S. White, K. Monaco, A.P. Holt, R. Farrar, P. Pagnamenta, A.T. Mirza, G.K. Ragoussis, J. Sousa, I. Sykes, N. Wing, K. Hallmayer, J. Cantor, R.M. Nelson, S.F. Geschwind, D.H. Abrahams, B.S. Volkmar, F. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J. Cook, E.H. Guter, S.J. Jacob, S. Nurnberger, J.I., Jr. McDougle, C.J. Posey, D.J. Lord, C. Corsello, C. Hus, V. Kolevzon, A. Soorya, L. Parkhomenko, E. Leventhal, B.L. Dawson, G. Vieland, V.J. Hakonarson, H. Glessner, J.T. Kim, C. Wang, K. Schellenberg, G.D. Devlin, B. Klei, L. Minshew, N. Sutcliffe, J.S. Haines, J.L. Lund, S.C. Thomson, S. Coon, H. Miller, J. McMahon, W.M. Munson, J. Estes, A. Wijsman, E.M. Autism Genome Project
- Abstract
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. © 2011 Macmillan Publishers Limited All rights reserved.
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- 2011
6. Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients
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BONORA, ELENA, GRAZIANO, CLAUDIO, MINOPOLI, FIORELLA, BACCHELLI, ELENA, MAGINI, PAMELA, DIQUIGIOVANNI, CHIARA, LOMARTIRE, SILVIA, Bianco F, VARGIOLU, MANUELA, PARCHI, PIERO, MARASCO, ELENA, Mantovani V, Rampoldi L, Trudu M, PARMEGGIANI, ANTONIA, Battaglia A, Mazzone L, Tortora G, MAESTRINI, ELENA, SERI, MARCO, Romeo G, IMGSAC, Bonora E, Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C, Lomartire S, Bianco F, Vargiolu M, Parchi P, Marasco E, Mantovani V, Rampoldi L, Trudu M, Parmeggiani A, Battaglia A, Mazzone L, Tortora G, Maestrini E, Seri M, Romeo G, IMGSAC, Bonora, E, Graziano, C, Minopoli, F, Bacchelli, E, Magini, P, Diquigiovanni, C, Lomartire, S, Bianco, F, Vargiolu, M, Parchi, P, Marasco, E, Mantovani, V, Rampoldi, L, Trudu, M, Parmeggiani, A, Battaglia, A, Mazzone, L, Tortora, G, Maestrini, E, Seri, M, and Romeo, G
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Male ,Vesicular Transport Proteins ,Inbred C57BL ,medicine.disease_cause ,Mice ,0302 clinical medicine ,autism spectrum disorders (ASDs) ,Receptors ,Intellectual disability ,Missense mutation ,Developmental ,Protein Interaction Maps ,Child ,Research Articles ,Sequence Deletion ,Genetics ,Mutation ,0303 health sciences ,monoallelic expression ,Gene Expression Regulation, Developmental ,Settore MED/39 - Neuropsichiatria Infantile ,Pedigree ,intellectual disability ,Child, Preschool ,DNA methylation ,Molecular Medicine ,CADPS2 ,Female ,Corrigendum ,Adult ,Child Development Disorders ,autism spectrum disorders ,Nerve Tissue Proteins ,Biology ,03 medical and health sciences ,Young Adult ,Dopamine D2 ,medicine ,Animals ,Humans ,Allele ,MUTATION SCREENING ,Preschool ,Gene ,Alleles ,Pervasive ,030304 developmental biology ,Aged ,Receptors, Dopamine D2 ,Calcium-Binding Proteins ,Genetic Variation ,Infant ,DNA Methylation ,medicine.disease ,Mice, Inbred C57BL ,Gene Expression Regulation ,Child Development Disorders, Pervasive ,Autism ,CpG Islands ,mutation screening ,Intellectual Disability ,030217 neurology & neurosurgery - Abstract
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.
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- 2014
7. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility
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O Korvatska, Alistair T. Pagnamenta, Claudio Toma, Fiorella Minopoli, Jennifer Reichert, Joseph D. Buxbaum, Janine A. Lamb, H Butler, A de Bildt, Geraldine Dawson, Laura Winchester, Anthony J. Bailey, Gabrielle Barnby, Elena Bacchelli, Inês Sousa, Nuala Sykes, Elena Maestrini, Erik J. Mulder, Thomas S. Scerri, Guiqing Cai, Gerard D. Schellenberg, Andrew P. Morris, Ruud B. Minderaa, Anthony P. Monaco, Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I, Toma C, Barnby G, Butler H, Winchester L, Scerri TS, Minopoli F, Reichert J, Cai G, Buxbaum JD, Korvatska O, Schellenberg GD, Dawson G, Bildt AD, Minderaa RB, Mulder EJ, Morris AP, Bailey AJ, and Monaco AP.
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Adult ,Male ,Linkage disequilibrium ,Candidate gene ,Genotype ,MULTILOCUS GENOTYPE DATA ,Gene Dosage ,Single-nucleotide polymorphism ,SPECTRUM DISORDERS ,Biology ,Polymorphism, Single Nucleotide ,CANDIDATE GENES ,single nucleotide polymorphisms ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endopeptidases ,chromosome 7 ,Humans ,Genetic Predisposition to Disease ,Heritability of autism ,Copy-number variation ,Child ,chromosome 2 ,Molecular Biology ,030304 developmental biology ,Genetic association ,Genetics ,0303 health sciences ,MUTATIONS ,GTPase-Activating Proteins ,Haplotype ,LINKAGE ANALYSES ,Genetic Variation ,LINKED MENTAL-RETARDATION ,PERVASIVE DEVELOPMENTAL DISORDERS ,disease susceptibility ,Tag SNP ,GENOME ,Psychiatry and Mental health ,Chromosomes, Human, Pair 2 ,CHROMOSOME 7Q ,Original Article ,Female ,autistic disorder ,Chromosomes, Human, Pair 7 ,linkage disequilibrium ,ARRAY-CGH ,030217 neurology & neurosurgery - Abstract
Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family. Molecular Psychiatry (2010) 15, 954-968; doi:10.1038/mp.2009.34; published online 28 April 2009
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- 2009
8. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders
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Christian Proepper, Dominique Bonneau, Catalina Betancur, Sarah Curran, Astrid M. Vicente, Henrik Anckarsäter, Elena Bacchelli, Sabine M. Klauck, Eftichia Duketis, Guiomar Oliveira, Fabien Fauchereau, Richard Delorme, Irma Järvelä, I. Carina Gillberg, Marina Konyukh, Stephen W. Scherer, Pauline Chaste, Elena Maestrini, Guillaume Huguet, Dalila Pinto, David Skuse, Marie-Christine Mouren, Béatrice Regnault, Nathalie Lemière, Jonas Melke, Christopher Gillberg, Bárbara Oliveira, Maria Råstam, Thomas Bourgeron, Marnie Kopp, Marc Delepine, Oriane Mercati, Raija Vanhala, Luigi Mazzone, Marion Leboyer, Richard Holt, Agatino Battaglia, Fiorella Minopoli, Katri Kantojärvi, Diana Zelenika, Liliana Ruta, Roberto Toro, Ana Filipa Sequeira, Françoise Devillard, Brigitte Assouline, Martin Poot, Elodie Ey, Regina Waltes, Vincent Guinchat, Tobias M. Boeckers, Jutta Heinrich, Anthony P. Monaco, Gudrun Nygren, Fritz Poustka, Mark Lathrop, David A. Collier, Claire S. Leblond, Patrick Bolton, Christine M. Freitag, Andreas G. Chiocchetti, Betancur, Catalina, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Ulm - Ulm University [Ulm, Allemagne], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Forensic Psychiatry, Lund University [Lund], Department of Pharmacology, Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Behavioural and Brain Sciences Unit, Institute of Child Health, University College of London [London] (UCL), University Medical Center [Utrecht], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King‘s College London, Social, Genetic and Developmental Psychiatry Centre (SGDP), Institute of psychiatry, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Biotechnology, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Division of Child Neurology and Psychiatry, Department of Paediatrics, Università degli studi di Catania = University of Catania (Unict), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute for Anatomy and Cell Biology, Department of Medical and Clinical Genetics, Leblond C.S., Heinrich J., Delorme R., Proepper C., Betancur C., Huguet G., Konyukh M., Chaste P| Ey E., Rastam M., Anckarsäter H., Nygren G., Gillberg IC., Melke J., Toro R., Regnault B., Fauchereau F., Mercati O., Lemière N., Skuse D., Poot M., Holt R., Monaco A.P., Järvelä I., Kantojärvi K., Vanhala R., Curran S., Collier D.A., Bolton P., Chiocchetti A., Klauck S.M., Poustka F., Freitag C.M., Waltes R., Kopp M., Duketis E., Bacchelli E., Minopoli F., Ruta L., Battaglia A., Mazzone L., Maestrini E., Sequeira A.F., Oliveira B., Vicente A., Oliveira G., Pinto D., Scherer S.W., Zelenika D., Delepine M., Lathrop M., Bonneau D., Guinchat V., Devillard F., Assouline B., Mouren M.C., Leboyer M., Gillberg C., Boeckers T.M., Bourgeron T., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Anatomy and Cell Biology, Ulm University, University of Lund, Institut Pasteur [Paris], University of Oxford [Oxford], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Università degli studi di Catania [Catania], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
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Male ,Gene Dosage ,Receptors, Nicotinic ,MESH: Protein Isoforms ,HIDDEN-MARKOV MODEL ,0302 clinical medicine ,MESH: Child ,Protein Isoforms ,Tissue Distribution ,MESH: Nerve Tissue Proteins ,Child ,Neurons ,0303 health sciences ,MESH: Alternative Splicing ,PSYCHIATRIC-DISORDERS ,CHRNA7 ,MESH: Sequence Deletion ,3. Good health ,Autism spectrum disorder ,Child, Preschool ,Medicine ,Adaptor Proteins, Signal Transducing ,Adult ,Alternative Splicing ,Cell Line ,Child Development Disorders, Pervasive ,Female ,Gene Expression Regulation ,Humans ,Nerve Tissue Proteins ,RNA Splice Sites ,Sequence Deletion ,Synapses ,alpha7 Nicotinic Acetylcholine Receptor ,Child Development Disorders ,education ,COPY-NUMBER VARIATION ,Molecular Genetics ,03 medical and health sciences ,Genetics ,AUTISM ,MESH: Tissue Distribution ,Molecular Biology ,Biology ,SNP GENOTYPING DATA ,Ecology, Evolution, Behavior and Systematics ,Pervasive ,MESH: Adaptor Proteins, Signal Transducing ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,RECURRENT MICRODELETIONS ,MESH: Child, Preschool ,Signal Transducing ,MESH: Adult ,SCAFFOLDING PROTEIN SHANK3 ,medicine.disease ,Human genetics ,MESH: Cell Line ,MESH: Female ,030217 neurology & neurosurgery ,Neuroscience ,Cancer Research ,MESH: Neurons ,MESH: RNA Splice Sites ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Bioinformatics ,Nicotinic ,MESH: Child Development Disorders, Pervasive ,MESH: Gene Dosage ,MESH: Synapses ,POSTSYNAPTIC DENSITY ,Receptors ,Copy-number variation ,Genetics (clinical) ,Psychiatry ,Adaptor Proteins ,MESH: Gene Expression Regulation ,Settore MED/39 - Neuropsichiatria Infantile ,SHANK2 ,Mental Health ,MESH: Receptors, Nicotinic ,Research Article ,lcsh:QH426-470 ,15Q13.3 MICRODELETIONS ,Genetic variation ,mental disorders ,medicine ,ddc:610 ,Preschool ,Gene ,030304 developmental biology ,MESH: Male ,lcsh:Genetics ,DE-NOVO MUTATIONS ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,biology.protein ,Autism ,3111 Biomedicine ,MENTAL-RETARDATION - Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While mutations in several genes have been identified in patients with ASD, little is known about their effects on neuronal function and their interaction with other genetic variations. Using a combination of genetic and functional approaches, we identified novel SHANK2 mutations including a de novo loss of one copy of the SHANK2 gene in a patient with autism and several mutations observed in patients that reduced neuronal cell contacts in vitro. Further genomic analysis of three patients carrying de novo SHANK2 deletions identified additional rare genomic imbalances previously associated with neuropsychiatric disorders. Taken together, these results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
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- 2012
9. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia
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Wouter G. Staal, Gerd Schulte-Körne, Thomas S. Scerri, Fritz Poustka, Panos Deloukas, Anthony P. Monaco, Roel A. Ophoff, Per Hoffmann, Denise Harold, Anthony J. Bailey, Ernesto Lowy, Kerstin U. Ludwig, Jiannis Ragoussis, Maretha de Jonge, Elena Bacchelli, Michael Conlon O'Donovan, Markus M. Nöthen, Ghazala Mirza, Alistair T. Pagnamenta, Silvia Paracchini, Julie Williams, Elena Maestrini, Andreas G. Chiocchetti, Renske H. Houben, Sabine M. Klauck, Fiorella Minopoli, Jade Chapman, Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, Chiocchetti A, Ludwig KU, Hoffmann P, Paracchini S, Lowy E, Harold DH, Chapman JA, Klauck SM, Poustka F, Houben RH, Staal WG, Ophoff RA, O'Donovan MC, Williams J, Nöthen MM, Schulte-Körne G, Deloukas P, Ragoussis J, Bailey AJ, Maestrini E, Monaco AP, and International Molecular Genetic Study Of Autism Consortium
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Adult ,Male ,Transcription, Genetic ,Cell Adhesion Molecules, Neuronal ,CNV ,CNTNAP5 ,Single-nucleotide polymorphism ,Autistic ,Polymorphism, Single Nucleotide ,Severity of Illness Index ,Dyslexia ,neurexin ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,mental disorders ,medicine ,SNP ,Missense mutation ,Humans ,Child ,Biological Psychiatry ,030304 developmental biology ,Sequence Deletion ,Genetics ,0303 health sciences ,GTPase-Activating Proteins ,DOCK4 ,DNA ,Middle Aged ,medicine.disease ,Pedigree ,Developmental disorder ,Fusion transcript ,Gene Expression Regulation ,Child Development Disorders, Pervasive ,Case-Control Studies ,Child, Preschool ,Autism ,Female ,Psychology ,030217 neurology & neurosurgery ,SNP array - Abstract
Background: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair. Methods: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects. Results: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects. Conclusions: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a highresolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach.
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- 2009
10. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
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Veronica J. Vieland, Stephen W. Scherer, Alison K. Merikangas, Naisha Shah, Edwin H. Cook, William M. McMahon, Kirsty Wing, Sabata C. Lund, Jacob A. S. Vorstman, Judith Conroy, Sabine M. Klauck, John B. Vincent, Astrid M. Vicente, Carine Mantoulan, Barbara Parrini, Jeremy R. Parr, Herman van Engeland, Jane McGrath, Guiomar Oliveira, Jonathan Green, James S. Sutcliffe, Peter Szatmari, Ann Le Couteur, Katerina Papanikolaou, Joseph Piven, Andrew Pickles, Gillian Baird, Inês Sousa, Gerard D. Schellenberg, Catarina Correia, Bennett L. Leventhal, Helen McConachie, Joseph T. Glessner, Fritz Poustka, Alistair T. Pagnamenta, Marion Leboyer, Nuala Sykes, Elena Maestrini, Penny Farrar, Maïté Tauber, Suzanne Foley, Richard Holt, Lonnie Zwaigenbaum, David J. Posey, John Tsiantis, Alexander Kolevzon, Agatino Battaglia, Maretha de Jonge, Hilary Coon, Gillian Hughes, John R. Gilbert, Patrick Bolton, Louise Gallagher, Jeff Munson, Kathy White, Michael L. Cuccaro, Annemarie Poustka, Daniel H. Geschwind, Richard Delorme, Annette Estes, Christine M. Freitag, Jillian P. Casey, Joana Almeida, Dalila Pinto, Simon Wallace, Sean Brennan, Stephen J. Guter, Stanley F. Nelson, Michael Rutter, Ghazala Mirza, Anthony J. Bailey, Christina Corsello, Kerstin Wittemeyer, Christian R. Marshall, Janine A. Lamb, Catherine Lord, Hakon Hakonarson, Jiannis Ragoussis, Catalina Betancur, Geraldine Dawson, Eftichia Duketis, Sean Ennis, Fiorella Minopoli, Christopher Gillberg, Vera Stoppioni, Bridget A. Fernandez, Frederico Duque, Eric Fombonne, Ellen M. Wijsman, Bernadette Rogé, Vanessa Hus, Susan E. Folstein, Jonathan L. Haines, Denis C. Shields, Tiago R. Magalhaes, Andrew Green, Thomas Bourgeron, Brian L. Yaspan, Ann P. Thompson, Gudrun Nygren, Judith Miller, Susanne Thomson, Roberta Igliozzi, Ana Filipa Sequeira, Kai Wang, Brett S. Abrahams, John I. Nurnberger, Michael Gill, Thomas H. Wassink, Christopher J. McDougle, Marc N. Coutanche, Anthony P. Monaco, Nadia Bolshakova, Cecilia Kim, Raffaella Tancredi, Rita M. Cantor, Phil Cali, Fred R. Volkmar, Tom Berney, Margaret A. Pericak-Vance, Joachim Hallmayer, Joseph D. Buxbaum, Elena Bacchelli, Latha Soorya, Richard Anney, Regina Regan, University of Bologna, Open University of Israël, IRCCS Fondazione Stella Maris [Pisa], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Goethe-University Frankfurt am Main, Memorial University of Newfoundland [St. John's], McGill University = Université McGill [Montréal, Canada], Johns Hopkins University (JHU), Autism Research Centre and Section of Developmental Psychiatry, University of Cambridge [UK] (CAM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Psychiatrie génétique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale, The Hospital for sick children [Toronto] (SickKids), University of Toronto, Australian Resources Research Centre, Kensington, Sécurité et Qualité des Produits d'Origine Végétale (SQPOV), Avignon Université (AU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital des Enfants, CHU Toulouse [Toulouse], School of Chemistry, Dalhousie University [Halifax], DLR Institut für Planetenforschung, Deutsches Zentrum für Luft- und Raumfahrt [Berlin] (DLR), Department of Human Genetics, University of Chicago, University of Alberta, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), University of Koblenz-Landau, McMaster University [Hamilton, Ontario], The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P. Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We wish to acknowledge the National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin Ireland for providing additional support and the Wellcome Trust Case–Control Consortium for providing data sets that were used as part of this study. J.P.C is supported by an EMBARK postgraduate award from the Irish Research Council for Science, Engineering and Technology (IRCSET)., The AGRE Consortium, Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S., McGill University, Institut National de la Recherche Agronomique (INRA)-Avignon Université (AU), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Bologna/Università di Bologna, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Candidate gene ,Genome-wide association study ,Linkage Disequilibrium ,MESH: Child Development Disorders, Pervasive ,Cohort Studies ,MESH: Genotype ,0302 clinical medicine ,MESH: Child ,Cluster Analysis ,Genetics(clinical) ,Copy-number variation ,Child ,MESH: Cohort Studies ,Genetics (clinical) ,Original Investigation ,SNPS ,Genetics ,0303 health sciences ,education.field_of_study ,MESH: Middle Aged ,MESH: Nuclear Family ,MESH: Polymorphism, Single Nucleotide ,Homozygote ,MESH: Genetic Predisposition to Disease ,Middle Aged ,Autism spectrum disorder (ASD) ,3. Good health ,MESH: Linkage Disequilibrium ,Female ,MESH: DNA Copy Number Variations ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,MESH: Homozygote ,Adult ,DNA Copy Number Variations ,Genotype ,Population ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Nuclear Family ,03 medical and health sciences ,HOMOZYGOSITY MAPPING ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,AUTISM ,GENOME-WIDE ASSOCIATION ,education ,030304 developmental biology ,MESH: Humans ,Genetic heterogeneity ,Haplotype ,MESH: Adult ,MESH: Haplotypes ,medicine.disease ,MESH: Cluster Analysis ,MESH: Male ,Haplotypes ,Child Development Disorders, Pervasive ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,MESH: Genome-Wide Association Study ,Autism ,MESH: Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users.
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11. Systematic application of SICA-PED protocol for central venous catheterization in neonates: A prospective clinical study on 104 cases.
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Spagnuolo F, Maietta A, Pugliese U, Lettieri E, Minopoli F, Coppola N, La Verde M, Macera M, Monari C, Onorato L, and Carpentieri M
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Background: Catheterization of central vessels can be associated with early and late, potentially fatal complications. A proactive approach is imperative to reduce the frequency and magnitude of adverse events. Recently, the GAVeCeLT has proposed a protocol called SICA-PED (i.e. Safe Insertion of Central Access in Pediatric patients) and includes seven evidence-based strategies., Methods: Through a single-center prospective observational study, the authors wanted to consolidate the efficacy and safety of these protocol in newborns. In a series of 104 newborns, the seven steps of the protocol were applied (1) pre-procedural ultrasound study of the RaCeVA veins, (2) correct aseptic technique, (3) ultrasound-guided venipuncture, (4) intraprocedural localization of the tip of the catheter with TTE (ECHO TIP) and (iECG) intracavitary electrocardiogram, (5) reasoned choice of the implant exit site with the RAVESTO Tunneling technique, (6) anchoring without stitches, and (7) exit point protection with the use of glue and transparent semipermeable membrane. The authors have included a further precaution in point (6) the subcutaneous anchoring system has added the counter-fixation of the catheter wings that we will call 6Plus Point., Results: All infants requiring implantation of elective us-guided central venous access were enrolled in the study. None of the 104 implanted central venous catheters experienced early complications (accidental arterial puncture, PNX, primary malposition); rare late complications such as ecchymosis, CRBSI, exit site infection or dislodgement were observed, No catheter-related thrombotic phenomena were observed. The CRBSI catheter-related infection rate was 2.47 × 1000 days catheter cases., Conclusion: The results of this prospective study strengthen the feasibility and efficacy of the SICA-Ped Protocol. Demonstrating that the systematic application of the evidence-based seven-step implantation strategy increases the success rate, minimizes early and late complications, which result in increased patient safety., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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12. Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients.
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Bonora E, Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C, Lomartire S, Bianco F, Vargiolu M, Parchi P, Marasco E, Mantovani V, Rampoldi L, Trudu M, Parmeggiani A, Battaglia A, Mazzone L, Tortora G, Maestrini E, Seri M, and Romeo G
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- Adult, Aged, Alleles, Animals, Child Development Disorders, Pervasive metabolism, Child, Preschool, CpG Islands, DNA Methylation, Female, Gene Expression Regulation, Developmental, Genetic Variation, Humans, Infant, Intellectual Disability metabolism, Male, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins genetics, Pedigree, Protein Interaction Maps, Sequence Deletion, Young Adult, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Child Development Disorders, Pervasive genetics, Intellectual Disability genetics, Receptors, Dopamine D2 metabolism, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism
- Abstract
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect., (© 2014 The Authors. Published under the terms of the CC BY license.)
- Published
- 2014
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13. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
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Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, and Ennis S
- Subjects
- Adult, Child, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, Female, Genotype, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Nuclear Family, Polymorphism, Single Nucleotide, Child Development Disorders, Pervasive genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Haplotypes genetics
- Abstract
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
- Published
- 2012
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14. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
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Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM, and Bourgeron T
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- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adult, Alternative Splicing genetics, Cell Line, Child, Child, Preschool, Female, Gene Dosage genetics, Gene Expression Regulation, Humans, Male, Neurons cytology, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Splice Sites genetics, Receptors, Nicotinic genetics, Receptors, Nicotinic metabolism, Synapses pathology, Tissue Distribution, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, Pervasive genetics, Nerve Tissue Proteins genetics, Sequence Deletion genetics, Synapses genetics
- Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Competing Interests: The authors have declared that no competing interests exist.
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- 2012
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15. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.
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Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, Chiocchetti A, Ludwig KU, Hoffmann P, Paracchini S, Lowy E, Harold DH, Chapman JA, Klauck SM, Poustka F, Houben RH, Staal WG, Ophoff RA, O'Donovan MC, Williams J, Nöthen MM, Schulte-Körne G, Deloukas P, Ragoussis J, Bailey AJ, Maestrini E, and Monaco AP
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- Adult, Case-Control Studies, Child, Child, Preschool, DNA analysis, Female, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Reference Values, Sequence Deletion, Severity of Illness Index, Transcription, Genetic, Cell Adhesion Molecules, Neuronal genetics, Child Development Disorders, Pervasive genetics, Dyslexia genetics, GTPase-Activating Proteins genetics, Gene Expression Regulation
- Abstract
Background: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair., Methods: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects., Results: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects., Conclusions: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a high-resolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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