Deciphering the genetic basis of developmental language disorder in children without intellectual disability, autism or apraxia of speech / Marion LESIEUR-SEBELLIN ; Karine SIQUIER-PERNET ; Geoffroy DELPLANCQ ; Marlene RIO ; Mélanie PARISOT ; Patrick NITSCHKÉ ; Cristina RODRIGUEZ-FONTENLA ; Alison BODINEAU ; Lucie NARCY ; Emilie SCHLUMBERGER ; Vincent CANTAGREL ; Valérie MALAN in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 10 p. Titre : Deciphering the genetic basis of developmental language disorder in children without intellectual disability, autism or apraxia of speech Type de document : texte imprimé Auteurs : Marion LESIEUR-SEBELLIN, Auteur ; Karine SIQUIER-PERNET, Auteur ; Geoffroy DELPLANCQ, Auteur ; Marlene RIO, Auteur ; Mélanie PARISOT, Auteur ; Patrick NITSCHKÉ, Auteur ; Cristina RODRIGUEZ-FONTENLA, Auteur ; Alison BODINEAU, Auteur ; Lucie NARCY, Auteur ; Emilie SCHLUMBERGER, Auteur ; Vincent CANTAGREL, Auteur ; Valérie MALAN, Auteur Article en page(s) : 10 p. Langues : Anglais (eng) Mots-clés : Humans  Male  Female  Child  Language Development Disorders/genetics  Apraxias/genetics  Child, Preschool  Intellectual Disability/genetics  DNA Copy Number Variations  Adolescent  Genetic Predisposition to Disease  15q13.3 locus  16p11.2 locus  Autism  Developmental language disorder  Intellectual disability  Neurodevelopmental disorders  ZNF292  use the data for research and publication purposes. Competing interests: The  authors declare no competing interests. Ethics approval and consent to  participate: Written informed consent was obtained from all individuals. All  studies were carried out in accordance with the declaration of Helsinki and were  approved by a national ethics committee (CPP Ile de France, RIPH2G reference DI  24.01180.000212, N°2024-A00519-38, CPP reference 29-2024, promoter reference  C23-79  promoter: Inserm). ClinicalTrials.gov Identifier: NCT06660108. Index. décimale : PER Périodiques Résumé : BACKGROUND: Developmental language disorder (DLD) refers to children who present with language difficulties that are not due to a known biomedical condition or associated with autism spectrum disorder (ASD) or intellectual disability (ID). The clinical heterogeneity of language disorders, the frequent presence of comorbidities, and the inconsistent terminology used over the years have impeded both research and clinical practice. Identifying sub-groups of children (i.e. DLD cases without childhood apraxia of speech (CAS)) with language difficulties is essential for elucidating the underlying genetic causes of this condition. DLD presents along a spectrum of severity, ranging from mild speech delays to profound disturbances in oral language structure in otherwise typically intelligent children. The prevalence of DLD is ~ 7-8% or 2% if severe forms are considered. This study aims to investigate a homogeneous cohort of DLD patients, excluding cases of ASD, ID or CAS, using multiple genomic approaches to better define the molecular basis of the disorder. METHODS: Fifteen families, including 27 children with severe DLD, were enrolled. The majority of cases (n = 24) were included in multiplex families while three cases were sporadic. This resulted in a cohort of 59 individuals for whom chromosomal microarray analysis and exome or genome sequencing were performed. RESULTS: We identified copy number variants (CNVs) predisposing to neurodevelopmental disorders with incomplete penetrance and variable expressivity in two families. These CNVs (i.e., 15q13.3 deletion and proximal 16p11.2 duplication) are interpreted as pathogenic. In one sporadic case, a de novo pathogenic variant in the ZNF292 gene, known to be associated with ID, was detected, broadening the spectrum of this syndrome. LIMITATIONS: The strict diagnostic criteria applied by our multidisciplinary team, including speech-language physicians, neuropsychologists, and paediatric neurologists, resulted in a relatively small sample size, which limit the strength of our findings. CONCLUSION: These findings highlight a common genetic architecture between DLD, ASD and ID, and underline the need for further investigation into overlapping neurodevelopmental pathways. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06660108. En ligne : https://dx.doi.org/10.1186/s13229-025-00642-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Deciphering the genetic basis of developmental language disorder in children without intellectual disability, autism or apraxia of speech [texte imprimé] / Marion LESIEUR-SEBELLIN, Auteur ; Karine SIQUIER-PERNET, Auteur ; Geoffroy DELPLANCQ, Auteur ; Marlene RIO, Auteur ; Mélanie PARISOT, Auteur ; Patrick NITSCHKÉ, Auteur ; Cristina RODRIGUEZ-FONTENLA, Auteur ; Alison BODINEAU, Auteur ; Lucie NARCY, Auteur ; Emilie SCHLUMBERGER, Auteur ; Vincent CANTAGREL, Auteur ; Valérie MALAN, Auteur . - 10 p. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 10 p. Mots-clés : Humans  Male  Female  Child  Language Development Disorders/genetics  Apraxias/genetics  Child, Preschool  Intellectual Disability/genetics  DNA Copy Number Variations  Adolescent  Genetic Predisposition to Disease  15q13.3 locus  16p11.2 locus  Autism  Developmental language disorder  Intellectual disability  Neurodevelopmental disorders  ZNF292  use the data for research and publication purposes. Competing interests: The  authors declare no competing interests. Ethics approval and consent to  participate: Written informed consent was obtained from all individuals. All  studies were carried out in accordance with the declaration of Helsinki and were  approved by a national ethics committee (CPP Ile de France, RIPH2G reference DI  24.01180.000212, N°2024-A00519-38, CPP reference 29-2024, promoter reference  C23-79  promoter: Inserm). ClinicalTrials.gov Identifier: NCT06660108. Index. décimale : PER Périodiques Résumé : BACKGROUND: Developmental language disorder (DLD) refers to children who present with language difficulties that are not due to a known biomedical condition or associated with autism spectrum disorder (ASD) or intellectual disability (ID). The clinical heterogeneity of language disorders, the frequent presence of comorbidities, and the inconsistent terminology used over the years have impeded both research and clinical practice. Identifying sub-groups of children (i.e. DLD cases without childhood apraxia of speech (CAS)) with language difficulties is essential for elucidating the underlying genetic causes of this condition. DLD presents along a spectrum of severity, ranging from mild speech delays to profound disturbances in oral language structure in otherwise typically intelligent children. The prevalence of DLD is ~ 7-8% or 2% if severe forms are considered. This study aims to investigate a homogeneous cohort of DLD patients, excluding cases of ASD, ID or CAS, using multiple genomic approaches to better define the molecular basis of the disorder. METHODS: Fifteen families, including 27 children with severe DLD, were enrolled. The majority of cases (n = 24) were included in multiplex families while three cases were sporadic. This resulted in a cohort of 59 individuals for whom chromosomal microarray analysis and exome or genome sequencing were performed. RESULTS: We identified copy number variants (CNVs) predisposing to neurodevelopmental disorders with incomplete penetrance and variable expressivity in two families. These CNVs (i.e., 15q13.3 deletion and proximal 16p11.2 duplication) are interpreted as pathogenic. In one sporadic case, a de novo pathogenic variant in the ZNF292 gene, known to be associated with ID, was detected, broadening the spectrum of this syndrome. LIMITATIONS: The strict diagnostic criteria applied by our multidisciplinary team, including speech-language physicians, neuropsychologists, and paediatric neurologists, resulted in a relatively small sample size, which limit the strength of our findings. CONCLUSION: These findings highlight a common genetic architecture between DLD, ASD and ID, and underline the need for further investigation into overlapping neurodevelopmental pathways. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06660108. En ligne : https://dx.doi.org/10.1186/s13229-025-00642-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology / Lam Son NGUYEN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 1p. Titre : Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology Type de document : texte imprimé Auteurs : Lam Son NGUYEN, Auteur ; Marylin LEPLEUX, Auteur ; Mélanie MAKHLOUF, Auteur ; Christelle MARTIN, Auteur ; Julien FREGEAC, Auteur ; Karine SIQUIER-PERNET, Auteur ; Alain PHILIPPE, Auteur ; François FERON, Auteur ; Bruno GEPNER, Auteur ; Claire ROUGEULLE, Auteur ; Yann HUMEAU, Auteur ; Laurence COLLEAUX, Auteur Article en page(s) : 1p. Langues : Anglais (eng) Mots-clés : 3' Untranslated Regions/genetics  Adult  Adult Stem Cells/metabolism  Animals  Astrocytes/metabolism  Autism Spectrum Disorder/genetics/pathology/physiopathology  Cells, Cultured  Female  Fibroblasts/metabolism  Genetic Vectors/genetics  Hippocampus/cytology/embryology  Humans  Lentivirus/genetics  Male  Mice  MicroRNAs/genetics/physiology  Neurons/metabolism/ultrastructure  Olfactory Mucosa/pathology  Organ Specificity  Real-Time Polymerase Chain Reaction  Transcriptome  Young Adult  Astrocyte  Autism spectrum disorders  MicroRNA  Neuron  Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology [texte imprimé] / Lam Son NGUYEN, Auteur ; Marylin LEPLEUX, Auteur ; Mélanie MAKHLOUF, Auteur ; Christelle MARTIN, Auteur ; Julien FREGEAC, Auteur ; Karine SIQUIER-PERNET, Auteur ; Alain PHILIPPE, Auteur ; François FERON, Auteur ; Bruno GEPNER, Auteur ; Claire ROUGEULLE, Auteur ; Yann HUMEAU, Auteur ; Laurence COLLEAUX, Auteur . - 1p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 1p. Mots-clés : 3' Untranslated Regions/genetics  Adult  Adult Stem Cells/metabolism  Animals  Astrocytes/metabolism  Autism Spectrum Disorder/genetics/pathology/physiopathology  Cells, Cultured  Female  Fibroblasts/metabolism  Genetic Vectors/genetics  Hippocampus/cytology/embryology  Humans  Lentivirus/genetics  Male  Mice  MicroRNAs/genetics/physiology  Neurons/metabolism/ultrastructure  Olfactory Mucosa/pathology  Organ Specificity  Real-Time Polymerase Chain Reaction  Transcriptome  Young Adult  Astrocyte  Autism spectrum disorders  MicroRNA  Neuron  Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

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