DNA methylation biomarkers of intellectual/developmental disability across the lifespan / Janine M. LASALLE in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : DNA methylation biomarkers of intellectual/developmental disability across the lifespan Type de document : texte imprimé Auteurs : Janine M. LASALLE, Auteur Langues : Anglais (eng) Mots-clés : Humans  DNA Methylation  Intellectual Disability/genetics/diagnosis/metabolism  Developmental Disabilities/genetics/diagnosis/metabolism  Biomarkers/metabolism  Epigenesis, Genetic  Female  Pregnancy  Aging  Autism  Biomarkers  Cell free DNA  Cord blood  DNA methylation  Down syndrome  Dup15q syndrome  Epigenetic clock  Epigenetics  Exposure  Genomic  Placenta  for publication: Not applicable. Competing interests: Dr. LaSalle is a co-founder  and Chief Scientific Officer at 2C Bioscience Inc. Index. décimale : PER Périodiques Résumé : Epigenetic mechanisms, including DNA methylation, act at the interface of genes and environment by allowing a static genome to respond and adapt to a dynamic environment during the lifespan of an individual. Genome-wide DNA methylation analyses on a wide range of human biospecimens are beginning to identify epigenetic biomarkers that can predict risk of intellectual/developmental disabilities (IDD). DNA methylation-based epigenetic signatures are becoming clinically useful in categorizing benign from pathogenic genetic variants following exome sequencing. While DNA methylation marks differ by tissue source, recent studies have shown that accessible perinatal tissues, such as placenta, cord blood, newborn blood spots, and cell free DNA may serve as accessible surrogate tissues for testing epigenetic biomarkers relevant to understanding genetic, environmental, and gene by environment interactions on the developing brain. These DNA methylation signatures may also provide important information about the biological pathways that become dysregulated prior to disease progression that could be used to develop early pharmacological interventions. Future applications could involve preventative screenings using DNA methylation biomarkers during pregnancy or the newborn period for IDDs and other neurodevelopmental disorders. DNA methylation biomarkers in adolescence and adulthood are also likely to be clinically useful for tracking biological aging or co-occurring health conditions that develop across the lifespan. In conclusion, DNA methylation biomarkers are expected to become more common in clinical diagnoses of IDD, to improve understanding of complex IDD etiologies, to improve endpoints for clinical trials, and to monitor potential health concerns for individuals with IDD as they age. En ligne : https://dx.doi.org/10.1186/s11689-025-09598-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] DNA methylation biomarkers of intellectual/developmental disability across the lifespan [texte imprimé] / Janine M. LASALLE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Humans  DNA Methylation  Intellectual Disability/genetics/diagnosis/metabolism  Developmental Disabilities/genetics/diagnosis/metabolism  Biomarkers/metabolism  Epigenesis, Genetic  Female  Pregnancy  Aging  Autism  Biomarkers  Cell free DNA  Cord blood  DNA methylation  Down syndrome  Dup15q syndrome  Epigenetic clock  Epigenetics  Exposure  Genomic  Placenta  for publication: Not applicable. Competing interests: Dr. LaSalle is a co-founder  and Chief Scientific Officer at 2C Bioscience Inc. Index. décimale : PER Périodiques Résumé : Epigenetic mechanisms, including DNA methylation, act at the interface of genes and environment by allowing a static genome to respond and adapt to a dynamic environment during the lifespan of an individual. Genome-wide DNA methylation analyses on a wide range of human biospecimens are beginning to identify epigenetic biomarkers that can predict risk of intellectual/developmental disabilities (IDD). DNA methylation-based epigenetic signatures are becoming clinically useful in categorizing benign from pathogenic genetic variants following exome sequencing. While DNA methylation marks differ by tissue source, recent studies have shown that accessible perinatal tissues, such as placenta, cord blood, newborn blood spots, and cell free DNA may serve as accessible surrogate tissues for testing epigenetic biomarkers relevant to understanding genetic, environmental, and gene by environment interactions on the developing brain. These DNA methylation signatures may also provide important information about the biological pathways that become dysregulated prior to disease progression that could be used to develop early pharmacological interventions. Future applications could involve preventative screenings using DNA methylation biomarkers during pregnancy or the newborn period for IDDs and other neurodevelopmental disorders. DNA methylation biomarkers in adolescence and adulthood are also likely to be clinically useful for tracking biological aging or co-occurring health conditions that develop across the lifespan. In conclusion, DNA methylation biomarkers are expected to become more common in clinical diagnoses of IDD, to improve understanding of complex IDD etiologies, to improve endpoints for clinical trials, and to monitor potential health concerns for individuals with IDD as they age. En ligne : https://dx.doi.org/10.1186/s11689-025-09598-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism / Amber HOGART

Public ISBD contenu dans The Neurochemical Basis of Autism / Gene J. BLATT Titre : Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism Type de document : texte imprimé Auteurs : Amber HOGART, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2010 Importance : p.113-127 Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=109 contenu dans The Neurochemical Basis of Autism / Gene J. BLATT Epigenetic Dysregulation of 15q11-13 GABAA Receptor Genes in Autism [texte imprimé] / Amber HOGART, Auteur ; Janine M. LASALLE, Auteur . - 2010 . - p.113-127. Langues : Anglais (eng) Mots-clés : Acide ?-aminobutyrique Index. décimale : SCI-D SCI-D - Neurosciences Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=109

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Expression Changes in Epigenetic Gene Pathways Associated With One-Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non-Typical Neurodevelopment / Yihui ZHU in Autism Research, 14-1 (January 2021)  

Public ISBD [article]  inAutism Research > 14-1 (January 2021) . - p.11-28 Titre : Expression Changes in Epigenetic Gene Pathways Associated With One-Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non-Typical Neurodevelopment Type de document : texte imprimé Auteurs : Yihui ZHU, Auteur ; Charles E. MORDAUNT, Auteur ; Blythe DURBIN-JOHNSON, Auteur ; Marie A. CAUDILL, Auteur ; Olga V. MALYSHEVA, Auteur ; Joshua W. MILLER, Auteur ; Ralph GREEN, Auteur ; S. Jill JAMES, Auteur ; Stepan MELNYK, Auteur ; M. Daniele FALLIN, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Rebecca J. SCHMIDT, Auteur ; Janine M. LASALLE, Auteur Article en page(s) : p.11-28 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  maternal blood  neurodevelopment  nutrition  one-carbon metabolites  prenatal  transcriptome Index. décimale : PER Périodiques Résumé : The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non-typical development (Non-TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. Genome-wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies-Learning Early Signs. Sixteen different one-carbon metabolites, including folic acid, betaine, 5'-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to one-carbon metabolites. Using differential gene expression analysis, six transcripts (TGR-AS1, SQSTM1, HLA-C, and RFESD) were associated with child outcomes (ASD, Non-TD, and TD) with genome-wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5-MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one-carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. LAY SUMMARY: Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non-typical neurodevelopment and were associated with maternal nutrients. En ligne : http://dx.doi.org/10.1002/aur.2428 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=441 [article] Expression Changes in Epigenetic Gene Pathways Associated With One-Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non-Typical Neurodevelopment [texte imprimé] / Yihui ZHU, Auteur ; Charles E. MORDAUNT, Auteur ; Blythe DURBIN-JOHNSON, Auteur ; Marie A. CAUDILL, Auteur ; Olga V. MALYSHEVA, Auteur ; Joshua W. MILLER, Auteur ; Ralph GREEN, Auteur ; S. Jill JAMES, Auteur ; Stepan MELNYK, Auteur ; M. Daniele FALLIN, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Rebecca J. SCHMIDT, Auteur ; Janine M. LASALLE, Auteur . - p.11-28. Langues : Anglais (eng) in Autism Research > 14-1 (January 2021) . - p.11-28 Mots-clés : autism spectrum disorder  maternal blood  neurodevelopment  nutrition  one-carbon metabolites  prenatal  transcriptome Index. décimale : PER Périodiques Résumé : The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non-typical development (Non-TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. Genome-wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies-Learning Early Signs. Sixteen different one-carbon metabolites, including folic acid, betaine, 5'-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to one-carbon metabolites. Using differential gene expression analysis, six transcripts (TGR-AS1, SQSTM1, HLA-C, and RFESD) were associated with child outcomes (ASD, Non-TD, and TD) with genome-wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5-MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one-carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. LAY SUMMARY: Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non-typical neurodevelopment and were associated with maternal nutrients. En ligne : http://dx.doi.org/10.1002/aur.2428 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=441

Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples / Haley SCOLES in Molecular Autism, (December 2011)  

Public ISBD [article]  inMolecular Autism > (December 2011) . - 41 p. Titre : Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples Type de document : texte imprimé Auteurs : Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence T. REITER, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2011 Article en page(s) : 41 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149 [article] Increased copy number for methylated maternal 15q duplications leads to changes in gene and protein expression in human cortical samples [texte imprimé] / Haley SCOLES, Auteur ; Nora URRACA, Auteur ; Samuel CHADWICK, Auteur ; Lawrence T. REITER, Auteur ; Janine M. LASALLE, Auteur . - 2011 . - 41 p. Langues : Anglais (eng) in Molecular Autism > (December 2011) . - 41 p. Index. décimale : PER Périodiques Résumé : BACKGROUND:Duplications of chromosome 15q11-q13 account for ~3% of autism cases. Chromosome 15q11-q13 contains imprinted genes necessary for normal mammalian neurodevelopment controlled by a differentially methylated imprinting center (PWS-IC). Maternal duplications of 15q11-q13 (dup15q) occur as both interstitial duplications (int dup(15)) and isodicentric chromosome 15 (idic15). Over-expression of the maternally expressed gene UBE3A is predicted to be the primary cause of the autistic features associated with dup15q. Previous analysis of two post-mortem dup15q frontal cortical samples showed heterogeneity between the two cases, with one showing levels of GABAA receptor genes, UBE3A, and SNRPN in a manner not predicted by copy number or parental imprint.METHODS:Postmortem human brain tissue (BA19, extrastriate visual cortex) was obtained from 8 dup15q, 10 idiopathic autism and 21 typical control samples. Quantitative PCR was used to confirm duplication status. Quantitative reverse transcriptase PCR and Western blot analyses were performed to measure 15q11-q13 transcript and protein levels, respectively. Methylation-sensitive high resolution melt curve analysis was performed on brain genomic DNA to identify the maternal:paternal ratio of methylation at PWS-IC.RESULTS:Dup15q brain samples showed a higher level of PWS-IC methylation than control or autism samples, indicating that the duplication of 15q was maternal in origin. UBE3A transcript and protein levels were significantly higher in dup15q than control and autism, as expected, although levels were variable and lower than expected based on copy number in some samples. In contrast, this increase in copy number did not result in consistently increased GABRB3 transcript or protein levels for dup15q samples. Furthermore, SNRPN was expected to be unchanged in expression in dup15q because it is expressed from the single unmethylated paternal allele, yet SNRPN levels were significantly reduced in dup15q samples compared to controls. PWS-IC methylation positively correlated with UBE3A and GABRB3, but negatively correlated with SNRPN levels. Idiopathic autism samples exhibited significantly lower GABRB3 and significantly more variable SNRPN levels compared to controls.CONCLUSIONS:While these results show that increased UBE3A/UBE3A is a consistent feature of dup15q syndrome, they also suggest that gene expression within 15q11-q13 is not based entirely on copy number but can be influenced by epigenetic mechanisms in brain. En ligne : http://dx.doi.org/10.1186/2040-2392-2-19 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=149

MeCP2 and Autism Spectrum Disorders / Sarrita ADAMS

Public ISBD in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM Titre : MeCP2 and Autism Spectrum Disorders Type de document : texte imprimé Auteurs : Sarrita ADAMS, Auteur ; Janine M. LASALLE, Auteur Année de publication : 2013 Importance : p.421-436 Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are characterized by complex genetic etiologies. Within ASD are a number of syndromic disorders with known genetic bases and autistic features. Rett syndrome (RTT) is an X-linked dominant ASD caused by mutations in the DNA methyl-binding protein MeCP2. A variety of mouse models of MeCP2 deficiency and over-expression have been generated and revealed the role of MeCP2 at the center of a number of other ASD-relevant pathways controlling synapse number and strength. In this chapter, we review the evidence for overlap in MeCP2 function with other ASD implicated genes, including FMR1, MEF2C, FOXG1, CNTNAP2, SHANK3, TSC2, UBE3A, and SYN1. In addition, we discuss what mouse models with these genetic deficiencies have revealed about the specific deficits of synaptic function in ASD and the normal orchestration of synaptic plasticity in the early postnatal brain. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189 in The Neuroscience of Autism Spectrum Disorders / Joseph D. BUXBAUM MeCP2 and Autism Spectrum Disorders [texte imprimé] / Sarrita ADAMS, Auteur ; Janine M. LASALLE, Auteur . - 2013 . - p.421-436. Langues : Anglais (eng) Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorders (ASD) are characterized by complex genetic etiologies. Within ASD are a number of syndromic disorders with known genetic bases and autistic features. Rett syndrome (RTT) is an X-linked dominant ASD caused by mutations in the DNA methyl-binding protein MeCP2. A variety of mouse models of MeCP2 deficiency and over-expression have been generated and revealed the role of MeCP2 at the center of a number of other ASD-relevant pathways controlling synapse number and strength. In this chapter, we review the evidence for overlap in MeCP2 function with other ASD implicated genes, including FMR1, MEF2C, FOXG1, CNTNAP2, SHANK3, TSC2, UBE3A, and SYN1. In addition, we discuss what mouse models with these genetic deficiencies have revealed about the specific deficits of synaptic function in ASD and the normal orchestration of synaptic plasticity in the early postnatal brain. Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=189

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MeCP2 modulates gene expression pathways in astrocytes / Dag H. YASUI in Molecular Autism, (January 2013)  

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MECP2 promoter methylation and X chromosome inactivation in autism / Raman P. NAGARAJAN in Autism Research, 1-3 (June 2008)  

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A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood / Charles E. MORDAUNT in Molecular Autism, 10 (2019)  

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Placental methylome analysis from a prospective autism study / Diane I. SCHROEDER in Molecular Autism, 7 (2016)  

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Rett syndrome : a Rosetta stone for understanding the molecular pathogenesis of autism / Janine M. LASALLE

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