Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons / Emily M.A. LEWIS in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 51 p. Titre : Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons Type de document : texte imprimé Auteurs : Emily M.A. LEWIS, Auteur ; Kesavan MEGANATHAN, Auteur ; Dustin BALDRIDGE, Auteur ; Paul GONTARZ, Auteur ; Bo ZHANG, Auteur ; Azad BONNI, Auteur ; John N. CONSTANTINO, Auteur ; Kristen L. KROLL, Auteur Article en page(s) : 51 p. Langues : Anglais (eng) Mots-clés : Cortical excitatory neurons  Cortical inhibitory neurons  Gene networks  Multiplex autism  Neurodevelopment  Transcriptomics  iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons [texte imprimé] / Emily M.A. LEWIS, Auteur ; Kesavan MEGANATHAN, Auteur ; Dustin BALDRIDGE, Auteur ; Paul GONTARZ, Auteur ; Bo ZHANG, Auteur ; Azad BONNI, Auteur ; John N. CONSTANTINO, Auteur ; Kristen L. KROLL, Auteur . - 51 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 51 p. Mots-clés : Cortical excitatory neurons  Cortical inhibitory neurons  Gene networks  Multiplex autism  Neurodevelopment  Transcriptomics  iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

The Brain Gene Registry: a data snapshot / Dustin BALDRIDGE in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : The Brain Gene Registry: a data snapshot Type de document : texte imprimé Auteurs : Dustin BALDRIDGE, Auteur ; Levi KASTER, Auteur ; Catherine SANCIMINO, Auteur ; Siddharth SRIVASTAVA, Auteur ; Sophie MOLHOLM, Auteur ; Aditi GUPTA, Auteur ; Inez OH, Auteur ; Virginia LANZOTTI, Auteur ; Daleep GREWAL, Auteur ; Erin Rooney RIGGS, Auteur ; Juliann M. SAVATT, Auteur ; Rachel HAUCK, Auteur ; Abigail SVEDEN, Auteur ; BRAIN GENE REGISTRY CONSORTIUM, Auteur ; John N. CONSTANTINO, Auteur ; Joseph PIVEN, Auteur ; Christina A. GURNETT, Auteur ; Maya CHOPRA, Auteur ; Heather HAZLETT, Auteur ; Philip R.O. PAYNE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Male  Female  Autism Spectrum Disorder/genetics  Autistic Disorder  Neurodevelopmental Disorders  Intellectual Disability  Brain  Registries  Methyltransferases  Brain gene registry  Electronic health records  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders. En ligne : https://dx.doi.org/10.1186/s11689-024-09530-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] The Brain Gene Registry: a data snapshot [texte imprimé] / Dustin BALDRIDGE, Auteur ; Levi KASTER, Auteur ; Catherine SANCIMINO, Auteur ; Siddharth SRIVASTAVA, Auteur ; Sophie MOLHOLM, Auteur ; Aditi GUPTA, Auteur ; Inez OH, Auteur ; Virginia LANZOTTI, Auteur ; Daleep GREWAL, Auteur ; Erin Rooney RIGGS, Auteur ; Juliann M. SAVATT, Auteur ; Rachel HAUCK, Auteur ; Abigail SVEDEN, Auteur ; BRAIN GENE REGISTRY CONSORTIUM, Auteur ; John N. CONSTANTINO, Auteur ; Joseph PIVEN, Auteur ; Christina A. GURNETT, Auteur ; Maya CHOPRA, Auteur ; Heather HAZLETT, Auteur ; Philip R.O. PAYNE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Male  Female  Autism Spectrum Disorder/genetics  Autistic Disorder  Neurodevelopmental Disorders  Intellectual Disability  Brain  Registries  Methyltransferases  Brain gene registry  Electronic health records  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders. En ligne : https://dx.doi.org/10.1186/s11689-024-09530-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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