Common genetic variants, acting additively, are a major source of risk for autism / Lambertus KLEI in Molecular Autism, (October 2012)  

Public ISBD [article]  inMolecular Autism > (October 2012) . - 13 p. Titre : Common genetic variants, acting additively, are a major source of risk for autism Type de document : texte imprimé Auteurs : Lambertus KLEI, Auteur ; Stephan J. SANDERS, Auteur ; Michael T. MURTHA, Auteur ; Vanessa HUS, Auteur ; Jennifer K. LOWE, Auteur ; A. Jeremy WILLSEY, Auteur ; Daniel MORENO DE LUCA, Auteur ; Timothy W. YU, Auteur ; Eric FOMBONNE, Auteur ; Daniel H. GESCHWIND, Auteur ; Dorothy E. GRICE, Auteur ; David H. LEDBETTER, Auteur ; Catherine LORD, Auteur ; Shrikant M. MANE, Auteur ; Christa Lese MARTIN, Auteur ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; Nadine M. MELHEM, Auteur ; Pauline CHASTE, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Edwin H. Jr COOK, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur Année de publication : 2012 Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : Narrow-sense heritability  Multiplex  Simplex  Quantitative genetics Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability. En ligne : http://dx.doi.org/10.1186/2040-2392-3-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] Common genetic variants, acting additively, are a major source of risk for autism [texte imprimé] / Lambertus KLEI, Auteur ; Stephan J. SANDERS, Auteur ; Michael T. MURTHA, Auteur ; Vanessa HUS, Auteur ; Jennifer K. LOWE, Auteur ; A. Jeremy WILLSEY, Auteur ; Daniel MORENO DE LUCA, Auteur ; Timothy W. YU, Auteur ; Eric FOMBONNE, Auteur ; Daniel H. GESCHWIND, Auteur ; Dorothy E. GRICE, Auteur ; David H. LEDBETTER, Auteur ; Catherine LORD, Auteur ; Shrikant M. MANE, Auteur ; Christa Lese MARTIN, Auteur ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; Nadine M. MELHEM, Auteur ; Pauline CHASTE, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Edwin H. Jr COOK, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur . - 2012 . - 13 p. Langues : Anglais (eng) in Molecular Autism > (October 2012) . - 13 p. Mots-clés : Narrow-sense heritability  Multiplex  Simplex  Quantitative genetics Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability. En ligne : http://dx.doi.org/10.1186/2040-2392-3-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics / Li LIU in Molecular Autism, (March 2014)  

Public ISBD [article]  inMolecular Autism > (March 2014) . - p.1-18 Titre : DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics Type de document : texte imprimé Auteurs : Li LIU, Auteur ; Jing LEI, Auteur ; Stephan J. SANDERS, Auteur ; Arthur Jeremy WILLSEY, Auteur ; Yan KOU, Auteur ; Abdullah Ercument CICEK, Auteur ; Lambertus KLEI, Auteur ; Cong LU, Auteur ; Xin HE, Auteur ; Mingfeng LI, Auteur ; Rebecca A. MUHLE, Auteur ; Avi MA’AYAN, Auteur ; James P. NOONAN, Auteur ; Nenad Å ESTAN, Auteur ; Kathryn MCFADDEN, Auteur ; Matthew W. STATE, Auteur ; Joseph D. BUXBAUM, Auteur ; Bernie DEVLIN, Auteur ; Kathryn ROEDER, Auteur Article en page(s) : p.1-18 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. En ligne : http://dx.doi.org/10.1186/2040-2392-5-22 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276 [article] DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics [texte imprimé] / Li LIU, Auteur ; Jing LEI, Auteur ; Stephan J. SANDERS, Auteur ; Arthur Jeremy WILLSEY, Auteur ; Yan KOU, Auteur ; Abdullah Ercument CICEK, Auteur ; Lambertus KLEI, Auteur ; Cong LU, Auteur ; Xin HE, Auteur ; Mingfeng LI, Auteur ; Rebecca A. MUHLE, Auteur ; Avi MA’AYAN, Auteur ; James P. NOONAN, Auteur ; Nenad Å ESTAN, Auteur ; Kathryn MCFADDEN, Auteur ; Matthew W. STATE, Auteur ; Joseph D. BUXBAUM, Auteur ; Bernie DEVLIN, Auteur ; Kathryn ROEDER, Auteur . - p.1-18. Langues : Anglais (eng) in Molecular Autism > (March 2014) . - p.1-18 Index. décimale : PER Périodiques Résumé : De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. En ligne : http://dx.doi.org/10.1186/2040-2392-5-22 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=276

How rare and common risk variation jointly affect liability for autism spectrum disorder / Lambertus KLEI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 66 p. Titre : How rare and common risk variation jointly affect liability for autism spectrum disorder Type de document : texte imprimé Auteurs : Lambertus KLEI, Auteur ; Lora Lee MCCLAIN, Auteur ; Behrang MAHJANI, Auteur ; Klea PANAYIDOU, Auteur ; Silvia DE RUBEIS, Auteur ; Anna-Carin Säll GRAHNAT, Auteur ; Gun KARLSSON, Auteur ; Yanchun LU, Auteur ; Nadine MELHEM, Auteur ; Xiu XU, Auteur ; Abraham REICHENBERG, Auteur ; Sven SANDIN, Auteur ; Christina M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur Article en page(s) : 66 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] How rare and common risk variation jointly affect liability for autism spectrum disorder [texte imprimé] / Lambertus KLEI, Auteur ; Lora Lee MCCLAIN, Auteur ; Behrang MAHJANI, Auteur ; Klea PANAYIDOU, Auteur ; Silvia DE RUBEIS, Auteur ; Anna-Carin Säll GRAHNAT, Auteur ; Gun KARLSSON, Auteur ; Yanchun LU, Auteur ; Nadine MELHEM, Auteur ; Xiu XU, Auteur ; Abraham REICHENBERG, Auteur ; Sven SANDIN, Auteur ; Christina M. HULTMAN, Auteur ; Joseph D. BUXBAUM, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur . - 66 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 66 p. Mots-clés : Autism spectrum disorder  De novo mutation  Genomic-Best Linear Unbiased Prediction (G-BLUP)  Liability  Polygenic risk score Index. décimale : PER Périodiques Résumé : BACKGROUND: Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. METHODS: To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth "burden"), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD ("PDV carriers"); ASD subjects who do not ("non-carriers"); and unaffected subjects who are assumed to be non-carriers. RESULTS: Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. LIMITATIONS: Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. CONCLUSIONS: Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. En ligne : http://dx.doi.org/10.1186/s13229-021-00466-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types / Siwei CHEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 76 p. Titre : De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types Type de document : texte imprimé Auteurs : Siwei CHEN, Auteur ; Jiebiao WANG, Auteur ; Ercument CICEK, Auteur ; Kathryn ROEDER, Auteur ; Haiyuan YU, Auteur ; Bernie DEVLIN, Auteur Article en page(s) : 76 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cell-type-specific transcriptome  De novo missense variation  Protein–protein interaction Index. décimale : PER Périodiques Résumé : BACKGROUND: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. METHODS: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein-protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an "ASD disrupted network." Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. RESULTS: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types-excitatory, inhibitory, and neural progenitor-we implicate several hundred genes in risk (FDR [Formula: see text]0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. LIMITATIONS: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. CONCLUSIONS: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00386-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types [texte imprimé] / Siwei CHEN, Auteur ; Jiebiao WANG, Auteur ; Ercument CICEK, Auteur ; Kathryn ROEDER, Auteur ; Haiyuan YU, Auteur ; Bernie DEVLIN, Auteur . - 76 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 76 p. Mots-clés : Autism spectrum disorder  Cell-type-specific transcriptome  De novo missense variation  Protein–protein interaction Index. décimale : PER Périodiques Résumé : BACKGROUND: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. METHODS: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein-protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an "ASD disrupted network." Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. RESULTS: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types-excitatory, inhibitory, and neural progenitor-we implicate several hundred genes in risk (FDR [Formula: see text]0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. LIMITATIONS: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. CONCLUSIONS: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD. En ligne : http://dx.doi.org/10.1186/s13229-020-00386-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder / Behrang MAHJANI in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 65 p. Titre : Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder Type de document : texte imprimé Auteurs : Behrang MAHJANI, Auteur ; Silvia DE RUBEIS, Auteur ; Christina GUSTAVSSON MAHJANI, Auteur ; Maureen MULHERN, Auteur ; Xiu XU, Auteur ; Lambertus KLEI, Auteur ; F. Kyle SATTERSTROM, Auteur ; Jack FU, Auteur ; Michael E. TALKOWSKI, Auteur ; Abraham REICHENBERG, Auteur ; Sven SANDIN, Auteur ; Christina M. HULTMAN, Auteur ; Dorothy E. GRICE, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 65 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder [texte imprimé] / Behrang MAHJANI, Auteur ; Silvia DE RUBEIS, Auteur ; Christina GUSTAVSSON MAHJANI, Auteur ; Maureen MULHERN, Auteur ; Xiu XU, Auteur ; Lambertus KLEI, Auteur ; F. Kyle SATTERSTROM, Auteur ; Jack FU, Auteur ; Michael E. TALKOWSKI, Auteur ; Abraham REICHENBERG, Auteur ; Sven SANDIN, Auteur ; Christina M. HULTMAN, Auteur ; Dorothy E. GRICE, Auteur ; Kathryn ROEDER, Auteur ; Bernie DEVLIN, Auteur ; Joseph D. BUXBAUM, Auteur . - 65 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 65 p. Mots-clés : Autism spectrum disorder  Copy number variant  Intellectual disability  Pages  Single nucleotide variant  Whole exome sequencing  that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: The Autism Sequencing Consortium identified 102 high-confidence autism spectrum disorder (ASD) genes, showing that individuals with ASD and with potentially damaging single nucleotide variation (pdSNV) in these genes had lower cognitive levels and delayed age at walking, when compared to ASD participants without pdSNV. Here, we made use of a Swedish sample of individuals with ASD (called PAGES, for Population-Based Autism Genetics & Environment Study) to evaluate the frequency of pdSNV and their impact on medical and psychiatric phenotypes, using an epidemiological frame and universal health reporting. We then combine findings with those for potentially damaging copy number variation (pdCNV). METHODS: SNV and CNV calls were generated from whole-exome sequencing and chromosome microarray data, respectively. Birth and medical register data were used to collect phenotypes. RESULTS: Of 808 individuals assessed by sequencing, 69 (9%) had pdSNV in the 102 ASC genes, and 144 (18%) had pdSNV in the 102 ASC genes or in a larger set of curated neurodevelopmental genes (from the Deciphering Developmental Disorders study, the gene2phenotype database, and the Radboud University gene lists). Three or more individuals had pdSNV in GRIN2B, POGZ, SATB1, DYNC1H1, SCN8A, or CREBBP. In comparison, out of the 996 individuals from whom CNV were called, 105 (11%) carried one or more pdCNV, including four or more individuals with CNV in the recurrent 15q11q13, 22q11.2, and 16p11.2 loci. Carriers of pdSNV were more likely to have intellectual disability (ID) and epilepsy, while carriers of pdCNV showed increased rates of congenital anomalies and scholastic skill disorders. Carriers of either pdSNV or pdCNV were more likely to have ID, scholastic skill disorders, and epilepsy. LIMITATIONS: The cohort only included individuals with autistic disorder, the more severe form of ASD, and phenotypes are defined from medical registers. Not all genes studied are definitively ASD genes, and we did not have de novo information to aid in classification. CONCLUSIONS: In this epidemiological sample, rare pdSNV were more common than pdCNV and the combined yield of potentially damaging variation was substantial at 27%. The results provide compelling rationale for the use of high-throughout sequencing as part of routine clinical workup for ASD and support the development of precision medicine in ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00465-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Sensitive periods for the effect of peer victimization on self-cognition: Moderation by age and gender / Kathryn ROEDER in Development and Psychopathology, 26-4 (Part 1) (November 2014)  

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