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

Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2 / Pauline CHASTE in Autism Research, 7-3 (June 2014)  

Public ISBD [article]  inAutism Research > 7-3 (June 2014) . - p.355-362 Titre : Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2 Type de document : texte imprimé Auteurs : Pauline CHASTE, Auteur ; Stephan J. SANDERS, Auteur ; Kommu N. MOHAN, Auteur ; Lambertus KLEI, Auteur ; Youeun SONG, 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 ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Christa Lese MARTIN, Auteur ; Bernie DEVLIN, Auteur ; Arthur L. BEAUDET, Auteur ; Edwin H. Jr COOK, Auteur ; Soo-Jeong KIM, Auteur Article en page(s) : p.355-362 Langues : Anglais (eng) Mots-clés : 15q11.2  deletion  duplication  penetrance  autism Index. décimale : PER Périodiques Résumé : The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1378 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=235 [article] Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2 [texte imprimé] / Pauline CHASTE, Auteur ; Stephan J. SANDERS, Auteur ; Kommu N. MOHAN, Auteur ; Lambertus KLEI, Auteur ; Youeun SONG, 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 ; Donna M. MARTIN, Auteur ; Eric M. MORROW, Auteur ; Christopher A. WALSH, Auteur ; James S. SUTCLIFFE, Auteur ; Matthew W. STATE, Auteur ; Christa Lese MARTIN, Auteur ; Bernie DEVLIN, Auteur ; Arthur L. BEAUDET, Auteur ; Edwin H. Jr COOK, Auteur ; Soo-Jeong KIM, Auteur . - p.355-362. Langues : Anglais (eng) in Autism Research > 7-3 (June 2014) . - p.355-362 Mots-clés : 15q11.2  deletion  duplication  penetrance  autism Index. décimale : PER Périodiques Résumé : The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1378 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=235

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

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders / Abha R. GUPTA in Molecular Autism, (April 2014)  

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