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Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism / R. CHEN in Molecular Autism, 8 (2017)
[article]
Titre : Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Type de document : Texte imprimé et/ou numérique Auteurs : R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*genetics/metabolism Endophenotypes/blood Exome Female Forkhead Transcription Factors/*genetics Genetic Predisposition to Disease Humans Jumonji Domain-Containing Histone Demethylases/*genetics Male *Mutation Nuclear Proteins/*genetics Repressor Proteins/*genetics Sequence Analysis, DNA/methods Serotonin/*blood Signal Transduction Ubiquitin-Specific Proteases/*genetics *5-ht *Autism *Autism spectrum disorder *Compound heterozygotes *De novo mutation *Endophenotype *Group-wise transmission/disequilibrium test *Hyperserotonemia *Rare variants *Serotonin *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329
in Molecular Autism > 8 (2017) . - 14p.[article] Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism [Texte imprimé et/ou numérique] / R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur . - 14p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 14p.
Mots-clés : Autism Spectrum Disorder/*genetics/metabolism Endophenotypes/blood Exome Female Forkhead Transcription Factors/*genetics Genetic Predisposition to Disease Humans Jumonji Domain-Containing Histone Demethylases/*genetics Male *Mutation Nuclear Proteins/*genetics Repressor Proteins/*genetics Sequence Analysis, DNA/methods Serotonin/*blood Signal Transduction Ubiquitin-Specific Proteases/*genetics *5-ht *Autism *Autism spectrum disorder *Compound heterozygotes *De novo mutation *Endophenotype *Group-wise transmission/disequilibrium test *Hyperserotonemia *Rare variants *Serotonin *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder / J. PIJUAN in Autism Research, 14-6 (June 2021)
[article]
Titre : PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur Article en page(s) : p.1088-1100 Langues : Anglais (eng) Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449
in Autism Research > 14-6 (June 2021) . - p.1088-1100[article] PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder [Texte imprimé et/ou numérique] / J. PIJUAN, Auteur ; J. D. ORTIGOZA-ESCOBAR, Auteur ; J. ORTIZ, Auteur ; A. ALCALÁ, Auteur ; M. J. CALVO, Auteur ; M. CUBELLS, Auteur ; C. HERNANDO-DAVALILLO, Auteur ; F. PALAU, Auteur ; J. HOENICKA, Auteur . - p.1088-1100.
Langues : Anglais (eng)
in Autism Research > 14-6 (June 2021) . - p.1088-1100
Mots-clés : Attention Deficit Disorder with Hyperactivity/genetics Autism Spectrum Disorder/genetics DNA Copy Number Variations Exome Genetic Predisposition to Disease/genetics Humans Nerve Tissue Proteins/genetics Receptors, Cell Surface Lrrc40 Plxna2 autism spectrum disorder diagnosis neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. En ligne : http://dx.doi.org/10.1002/aur.2502 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder / R. P. GOIN-KOCHEL in Journal of Autism and Developmental Disorders, 47-11 (November 2017)
[article]
Titre : Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : R. P. GOIN-KOCHEL, Auteur ; S. TRINH, Auteur ; S. BARBER, Auteur ; Raphael BERNIER, Auteur Article en page(s) : p.3600-3607 Langues : Anglais (eng) Mots-clés : Asd Autism Exome Genetics Mutation Regression Simplex Index. décimale : PER Périodiques Résumé : Approximately one-third of children with autism spectrum disorder (ASD) reportedly lose skills within the first 3 years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses. En ligne : http://dx.doi.org/10.1007/s10803-017-3256-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=325
in Journal of Autism and Developmental Disorders > 47-11 (November 2017) . - p.3600-3607[article] Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder [Texte imprimé et/ou numérique] / R. P. GOIN-KOCHEL, Auteur ; S. TRINH, Auteur ; S. BARBER, Auteur ; Raphael BERNIER, Auteur . - p.3600-3607.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 47-11 (November 2017) . - p.3600-3607
Mots-clés : Asd Autism Exome Genetics Mutation Regression Simplex Index. décimale : PER Périodiques Résumé : Approximately one-third of children with autism spectrum disorder (ASD) reportedly lose skills within the first 3 years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses. En ligne : http://dx.doi.org/10.1007/s10803-017-3256-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=325