An electronic health record (EHR) phenotype algorithm to identify patients with attention deficit hyperactivity disorders (ADHD) and psychiatric comorbidities / Isabella SLABY in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : An electronic health record (EHR) phenotype algorithm to identify patients with attention deficit hyperactivity disorders (ADHD) and psychiatric comorbidities Type de document : texte imprimé Auteurs : Isabella SLABY, Auteur ; Heather S. HAIN, Auteur ; Debra ABRAMS, Auteur ; Frank D. MENTCH, Auteur ; Joseph T. GLESSNER, Auteur ; Patrick M.A. SLEIMAN, Auteur ; Hakon HAKONARSON, Auteur Langues : Anglais (eng) Mots-clés : Algorithms  Attention Deficit Disorder with  Hyperactivity/complications/diagnosis/epidemiology  Case-Control Studies  Child  Comorbidity  Electronic Health Records  Humans  Phenotype  Prospective Studies  Retrospective Studies Index. décimale : PER Périodiques Résumé : BACKGROUND: In over half of pediatric cases, ADHD presents with comorbidities, and often, it is unclear whether the symptoms causing impairment are due to the comorbidity or the underlying ADHD. Comorbid conditions increase the likelihood for a more severe and persistent course and complicate treatment decisions. Therefore, it is highly important to establish an algorithm that identifies ADHD and comorbidities in order to improve research on ADHD using biorepository and other electronic record data. METHODS: It is feasible to accurately distinguish between ADHD in isolation from ADHD with comorbidities using an electronic algorithm designed to include other psychiatric disorders. We sought to develop an EHR phenotype algorithm to discriminate cases with ADHD in isolation from cases with ADHD with comorbidities more effectively for efficient future searches in large biorepositories. We developed a multi-source algorithm allowing for a more complete view of the patient's EHR, leveraging the biobank of the Center for Applied Genomics (CAG) at Children's Hospital of Philadelphia (CHOP). We mined EHRs from 2009 to 2016 using International Statistical Classification of Diseases and Related Health Problems (ICD) codes, medication history and keywords specific to ADHD, and comorbid psychiatric disorders to facilitate genotype-phenotype correlation efforts. Chart abstractions and behavioral surveys added evidence in support of the psychiatric diagnoses. Most notably, the algorithm did not exclude other psychiatric disorders, as is the case in many previous algorithms. Controls lacked psychiatric and other neurological disorders. Participants enrolled in various CAG studies at CHOP and completed a broad informed consent, including consent for prospective analyses of EHRs. We created and validated an EHR-based algorithm to classify ADHD and comorbid psychiatric status in a pediatric healthcare network to be used in future genetic analyses and discovery-based studies. RESULTS: In this retrospective case-control study that included data from 51,293 subjects, 5840 ADHD cases were discovered of which 46.1% had ADHD alone and 53.9% had ADHD with psychiatric comorbidities. Our primary study outcome was to examine whether the algorithm could identify and distinguish ADHD exclusive cases from ADHD comorbid cases. The results indicate ICD codes coupled with medication searches revealed the most cases. We discovered ADHD-related keywords did not increase yield. However, we found including ADHD-specific medications increased our number of cases by 21%. Positive predictive values (PPVs) were 95% for ADHD cases and 93% for controls. CONCLUSION: We established a new algorithm and demonstrated the feasibility of the electronic algorithm approach to accurately diagnose ADHD and comorbid conditions, verifying the efficiency of our large biorepository for further genetic discovery-based analyses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02286817 . First posted on 10 November 2014. CLINICALTRIALS: gov, NCT02777931 . First posted on 19 May 2016. CLINICALTRIALS: gov, NCT03006367 . First posted on 30 December 2016. CLINICALTRIALS: gov, NCT02895906 . First posted on 12 September 2016. En ligne : https://dx.doi.org/10.1186/s11689-022-09447-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] An electronic health record (EHR) phenotype algorithm to identify patients with attention deficit hyperactivity disorders (ADHD) and psychiatric comorbidities [texte imprimé] / Isabella SLABY, Auteur ; Heather S. HAIN, Auteur ; Debra ABRAMS, Auteur ; Frank D. MENTCH, Auteur ; Joseph T. GLESSNER, Auteur ; Patrick M.A. SLEIMAN, Auteur ; Hakon HAKONARSON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Algorithms  Attention Deficit Disorder with  Hyperactivity/complications/diagnosis/epidemiology  Case-Control Studies  Child  Comorbidity  Electronic Health Records  Humans  Phenotype  Prospective Studies  Retrospective Studies Index. décimale : PER Périodiques Résumé : BACKGROUND: In over half of pediatric cases, ADHD presents with comorbidities, and often, it is unclear whether the symptoms causing impairment are due to the comorbidity or the underlying ADHD. Comorbid conditions increase the likelihood for a more severe and persistent course and complicate treatment decisions. Therefore, it is highly important to establish an algorithm that identifies ADHD and comorbidities in order to improve research on ADHD using biorepository and other electronic record data. METHODS: It is feasible to accurately distinguish between ADHD in isolation from ADHD with comorbidities using an electronic algorithm designed to include other psychiatric disorders. We sought to develop an EHR phenotype algorithm to discriminate cases with ADHD in isolation from cases with ADHD with comorbidities more effectively for efficient future searches in large biorepositories. We developed a multi-source algorithm allowing for a more complete view of the patient's EHR, leveraging the biobank of the Center for Applied Genomics (CAG) at Children's Hospital of Philadelphia (CHOP). We mined EHRs from 2009 to 2016 using International Statistical Classification of Diseases and Related Health Problems (ICD) codes, medication history and keywords specific to ADHD, and comorbid psychiatric disorders to facilitate genotype-phenotype correlation efforts. Chart abstractions and behavioral surveys added evidence in support of the psychiatric diagnoses. Most notably, the algorithm did not exclude other psychiatric disorders, as is the case in many previous algorithms. Controls lacked psychiatric and other neurological disorders. Participants enrolled in various CAG studies at CHOP and completed a broad informed consent, including consent for prospective analyses of EHRs. We created and validated an EHR-based algorithm to classify ADHD and comorbid psychiatric status in a pediatric healthcare network to be used in future genetic analyses and discovery-based studies. RESULTS: In this retrospective case-control study that included data from 51,293 subjects, 5840 ADHD cases were discovered of which 46.1% had ADHD alone and 53.9% had ADHD with psychiatric comorbidities. Our primary study outcome was to examine whether the algorithm could identify and distinguish ADHD exclusive cases from ADHD comorbid cases. The results indicate ICD codes coupled with medication searches revealed the most cases. We discovered ADHD-related keywords did not increase yield. However, we found including ADHD-specific medications increased our number of cases by 21%. Positive predictive values (PPVs) were 95% for ADHD cases and 93% for controls. CONCLUSION: We established a new algorithm and demonstrated the feasibility of the electronic algorithm approach to accurately diagnose ADHD and comorbid conditions, verifying the efficiency of our large biorepository for further genetic discovery-based analyses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02286817 . First posted on 10 November 2014. CLINICALTRIALS: gov, NCT02777931 . First posted on 19 May 2016. CLINICALTRIALS: gov, NCT03006367 . First posted on 30 December 2016. CLINICALTRIALS: gov, NCT02895906 . First posted on 12 September 2016. En ligne : https://dx.doi.org/10.1186/s11689-022-09447-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males / Ren-Hua CHUNG in Molecular Autism, (November 2011)  

Public ISBD [article]  inMolecular Autism > (November 2011) . - 10 p. Titre : An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males Type de document : texte imprimé Auteurs : Ren-Hua CHUNG, Auteur ; Deqiong MA, Auteur ; Kai WANG, Auteur ; Dale HEDGES, Auteur ; James M. JAWORSKI, Auteur ; John R. GILBERT, Auteur ; Michael L. CUCCARO, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Gerard SCHELLENBERG, Auteur ; Hakon HAKONARSON, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; Eden R. MARTIN, Auteur Année de publication : 2011 Article en page(s) : 10 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.METHODS:We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.RESULTS:One SNP, rs17321050, in the transducin beta-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 x 10-6) and joint analysis (P value = 4.53 x 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 x 10-3) and passed the replication threshold in the validation data set (P = 2.56 x 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.CONCLUSIONS:TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-2-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 [article] An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males [texte imprimé] / Ren-Hua CHUNG, Auteur ; Deqiong MA, Auteur ; Kai WANG, Auteur ; Dale HEDGES, Auteur ; James M. JAWORSKI, Auteur ; John R. GILBERT, Auteur ; Michael L. CUCCARO, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; Gerard SCHELLENBERG, Auteur ; Hakon HAKONARSON, Auteur ; Jonathan L. HAINES, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; Eden R. MARTIN, Auteur . - 2011 . - 10 p. Langues : Anglais (eng) in Molecular Autism > (November 2011) . - 10 p. Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.METHODS:We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.RESULTS:One SNP, rs17321050, in the transducin beta-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 x 10-6) and joint analysis (P value = 4.53 x 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 x 10-3) and passed the replication threshold in the validation data set (P = 2.56 x 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.CONCLUSIONS:TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk. En ligne : http://dx.doi.org/10.1186/2040-2392-2-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149

Common variation contributes to the genetic architecture of social communication traits / Beate ST POURCAIN in Molecular Autism, (September 2013)  

Public ISBD [article]  inMolecular Autism > (September 2013) Titre : Common variation contributes to the genetic architecture of social communication traits Type de document : texte imprimé Auteurs : Beate ST POURCAIN, Auteur ; Andrew J.O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Common variation contributes to the genetic architecture of social communication traits [texte imprimé] / Beate ST POURCAIN, Auteur ; Andrew J.O. WHITEHOUSE, Auteur ; Wei ANG, Auteur ; Nicole WARRINGTON, Auteur ; Joseph GLESSNER, Auteur ; Kai WANG, Auteur ; Nicholas TIMPSON, Auteur ; David EVANS, Auteur ; John KEMP, Auteur ; Susan RING, Auteur ; Wendy MCARDLE, Auteur ; Jean GOLDING, Auteur ; Hakon HAKONARSON, Auteur ; Craig E. PENNELL, Auteur ; George SMITH, Auteur. Langues : Anglais (eng) in Molecular Autism > (September 2013) Index. décimale : PER Périodiques Résumé : Social communication difficulties represent an autistic trait that is highly heritable and persistent during the course of development. However, little is known about the underlying genetic architecture of this phenotype. We performed a genome-wide association study on parent-reported social communication problems using items of the children's communication checklist (age 10 to 11 years) studying single and/or joint marker effects. Analyses were conducted in a large UK population-based birth cohort (Avon Longitudinal Study of Parents and their Children, ALSPAC, N = 5,584) and followed-up within a sample of children with comparable measures from Western Australia (RAINE, N = 1364). Two of our seven independent top signals (P-discovery 1.0E-05) were replicated (0.009 P-replication [less than or equal to]0.02) within RAINE and suggested evidence for association at 6p22.1 (rs9257616, meta-P = 2.5E-07) and 14q22.1 (rs2352908, meta-P = 1.1E-06). The signal at 6p22.1 was identified within the olfactory receptor gene cluster within the broader major histocompatibility complex (MHC) region. The strongest candidate locus within this genomic area was TRIM27. This gene encodes an ubiquitin E3 ligase, which is an interaction partner of methyl-CpG-binding domain (MBD) proteins, such as MBD3 and MBD4, and rare protein-coding mutations within MBD3 and MBD4 have been linked to autism. The signal at 14q22.1 was found within a gene-poor region.Single-variant findings were complemented by estimations of the narrow-sense heritability in ALSPAC suggesting that approximately a fifth of the phenotypic variance in social communication traits is accounted for by joint additive effects of genotyped single nucleotide polymorphisms throughout the genome (h2(SE) = 0.18(0.066), P = 0.0027). Overall, our study provides both joint and single-SNP-based evidence for the contribution of common polymorphisms to variation in social communication phenotypes. En ligne : http://dx.doi.org/10.1186/2040-2392-4-34 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Convergent genetic pathways linking neuropsychiatric and ocular disorders in children / Meng PAN in Journal of Child Psychology and Psychiatry, 67-9 (September 2026)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 67-9 (September 2026) . - p.1460-1475 Titre : Convergent genetic pathways linking neuropsychiatric and ocular disorders in children Type de document : texte imprimé Auteurs : Meng PAN, Auteur ; Wentao ZHOU, Auteur ; Hui-Qi QU, Auteur ; Zhanjie XIU, Auteur ; Rui SUN, Auteur ; Hakon HAKONARSON, Auteur ; Jin LI, Auteur ; Xuefeng SHI, Auteur Article en page(s) : p.1460-1475 Langues : Anglais (eng) Mots-clés : Pediatric neuropsychiatric disorders  refractive error  genetic correlation  pleiotropy  genome-wide association study  attention deficit/hyperactivity disorder Index. décimale : PER Périodiques Résumé : Background Clinical and epidemiological studies conducted in children have suggested a potential link between neuropsychiatric and ocular disorders. However, the existence and directionality of this relationship remain inconsistent, likely due to the complex interplay between genetic predisposition and environmental factors that may influence both conditions. Methods We investigated the overall and local genetic correlations and causal relationship between eight neuropsychiatric disorders and five ocular disorders based on large-scale genome-wide association study cohorts from Psychiatric Genomics Consortium and UK Biobank. An in-house independent cohort (2,726 attention deficit hyperactivity disorder (ADHD) cases and 16,299 controls) was also assessed to confirm the disease relationships. We further performed joint analyses to pinpoint the shared genetic loci. Finally, we explored their underlying biological pathways by SNP- and Gene-based enrichment analyses. Results We discovered significant positive genetic correlations between autism spectrum disorder (ASD) and myopia/astigmatism; inverse genetic correlation and potential causal relationship between ADHD and myopia/astigmatism. The aggregated protective effect of ADHD on myopia and astigmatism was demonstrated using Mendelian randomization, and was validated in the independent in-house cohort. In total, 124 loci were found to be shared between psychiatric diseases and refractive errors. Enrichment analyses highlighted early neurodevelopmental processes as key shared genetic mechanisms that may play a critical role in the development of childhood-onset neuropsychiatric disorders and refractive errors. Conclusions Our findings indicate a shared genetic architecture underlying the development of childhood-onset neuropsychiatric disorders and refractive errors. These results help clarify the clinically observed associations between ADHD, ASD, and refractive errors and provide evidence that shared early neurodevelopmental processes contribute to both conditions. Together, the findings offer a novel perspective on the neurogenetic basis of refractive error and its connection to early brain development. En ligne : https://doi.org/10.1111/jcpp.70151 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=592 [article] Convergent genetic pathways linking neuropsychiatric and ocular disorders in children [texte imprimé] / Meng PAN, Auteur ; Wentao ZHOU, Auteur ; Hui-Qi QU, Auteur ; Zhanjie XIU, Auteur ; Rui SUN, Auteur ; Hakon HAKONARSON, Auteur ; Jin LI, Auteur ; Xuefeng SHI, Auteur . - p.1460-1475. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 67-9 (September 2026) . - p.1460-1475 Mots-clés : Pediatric neuropsychiatric disorders  refractive error  genetic correlation  pleiotropy  genome-wide association study  attention deficit/hyperactivity disorder Index. décimale : PER Périodiques Résumé : Background Clinical and epidemiological studies conducted in children have suggested a potential link between neuropsychiatric and ocular disorders. However, the existence and directionality of this relationship remain inconsistent, likely due to the complex interplay between genetic predisposition and environmental factors that may influence both conditions. Methods We investigated the overall and local genetic correlations and causal relationship between eight neuropsychiatric disorders and five ocular disorders based on large-scale genome-wide association study cohorts from Psychiatric Genomics Consortium and UK Biobank. An in-house independent cohort (2,726 attention deficit hyperactivity disorder (ADHD) cases and 16,299 controls) was also assessed to confirm the disease relationships. We further performed joint analyses to pinpoint the shared genetic loci. Finally, we explored their underlying biological pathways by SNP- and Gene-based enrichment analyses. Results We discovered significant positive genetic correlations between autism spectrum disorder (ASD) and myopia/astigmatism; inverse genetic correlation and potential causal relationship between ADHD and myopia/astigmatism. The aggregated protective effect of ADHD on myopia and astigmatism was demonstrated using Mendelian randomization, and was validated in the independent in-house cohort. In total, 124 loci were found to be shared between psychiatric diseases and refractive errors. Enrichment analyses highlighted early neurodevelopmental processes as key shared genetic mechanisms that may play a critical role in the development of childhood-onset neuropsychiatric disorders and refractive errors. Conclusions Our findings indicate a shared genetic architecture underlying the development of childhood-onset neuropsychiatric disorders and refractive errors. These results help clarify the clinically observed associations between ADHD, ASD, and refractive errors and provide evidence that shared early neurodevelopmental processes contribute to both conditions. Together, the findings offer a novel perspective on the neurogenetic basis of refractive error and its connection to early brain development. En ligne : https://doi.org/10.1111/jcpp.70151 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=592

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population / Nori MATSUNAMI in Molecular Autism, (January 2014)  

Public ISBD [article]  inMolecular Autism > (January 2014) Titre : Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population Type de document : texte imprimé Auteurs : Nori MATSUNAMI, Auteur ; Charles HENSEL, Auteur ; Lisa BAIRD, Auteur ; Jeff STEVENS, Auteur ; Brith OTTERUD, Auteur ; Tami LEPPERT, Auteur ; Tena VARVIL, Auteur ; Dexter HADLEY, Auteur ; Joseph GLESSNER, Auteur ; Renata PELLEGRINO, Auteur ; Cecilia KIM, Auteur ; Kelly THOMAS, Auteur ; Fengxiang WANG, Auteur ; Frederick OTIENO, Auteur ; Karen HO, Auteur ; Gerald CHRISTENSEN, Auteur ; Dongying LI, Auteur ; Rytis PREKERIS, Auteur ; Christophe LAMBERT, Auteur ; Hakon HAKONARSON, Auteur ; Mark LEPPERT, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken. We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population. We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci. Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants. En ligne : http://dx.doi.org/10.1186/2040-2392-5-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population [texte imprimé] / Nori MATSUNAMI, Auteur ; Charles HENSEL, Auteur ; Lisa BAIRD, Auteur ; Jeff STEVENS, Auteur ; Brith OTTERUD, Auteur ; Tami LEPPERT, Auteur ; Tena VARVIL, Auteur ; Dexter HADLEY, Auteur ; Joseph GLESSNER, Auteur ; Renata PELLEGRINO, Auteur ; Cecilia KIM, Auteur ; Kelly THOMAS, Auteur ; Fengxiang WANG, Auteur ; Frederick OTIENO, Auteur ; Karen HO, Auteur ; Gerald CHRISTENSEN, Auteur ; Dongying LI, Auteur ; Rytis PREKERIS, Auteur ; Christophe LAMBERT, Auteur ; Hakon HAKONARSON, Auteur ; Mark LEPPERT, Auteur. Langues : Anglais (eng) in Molecular Autism > (January 2014) Index. décimale : PER Périodiques Résumé : Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken. We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population. We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci. Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants. En ligne : http://dx.doi.org/10.1186/2040-2392-5-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region / L. Alison MCINNES in Molecular Autism, (March 2010)  

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Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders / Joseph T. GLESSNER in Journal of Neurodevelopmental Disorders, 15 (2023)  

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The Genetics of Autism Spectrum Disorders / John J.M. CONNOLLY  

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The Philadelphia Neurodevelopmental Cohort: constructing a deep phenotyping collaborative / Monica E. CALKINS in Journal of Child Psychology and Psychiatry, 56-12 (December 2015)  

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Variability in the common genetic architecture of social-communication spectrum phenotypes during childhood and adolescence / Beate ST POURCAIN in Molecular Autism, (February 2014)  

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Whole-genome sequencing in an autism multiplex family / Lingling SHI in Molecular Autism, (April 2013)  

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