Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism / K. LUHRS in Autism Research and Treatment, 2017 (2017)  

Public ISBD [article]  inAutism Research and Treatment > 2017 (2017) Titre : Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism Type de document : Texte imprimé et/ou numérique Auteurs : K. LUHRS, Auteur ; T. WARD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; H. A. F. STESSMAN, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n = 62), de novo deletion copy number variations (DEL, n = 74), de novo likely gene-disrupting mutations (LGDM, n = 267), and children without a known genetic etiology (NON, n = 2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships. En ligne : http://dx.doi.org/10.1155/2017/9371964 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333 [article] Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism [Texte imprimé et/ou numérique] / K. LUHRS, Auteur ; T. WARD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; H. A. F. STESSMAN, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur. Langues : Anglais (eng) in Autism Research and Treatment > 2017 (2017) Index. décimale : PER Périodiques Résumé : The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n = 62), de novo deletion copy number variations (DEL, n = 74), de novo likely gene-disrupting mutations (LGDM, n = 267), and children without a known genetic etiology (NON, n = 2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships. En ligne : http://dx.doi.org/10.1155/2017/9371964 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333

Differential effects by sex with Kmt5b loss / R. N. WICKRAMASEKARA in Autism Research, 14-8 (August 2021)  

Public ISBD [article]  inAutism Research > 14-8 (August 2021) . - p.1554-1571 Titre : Differential effects by sex with Kmt5b loss Type de document : Texte imprimé et/ou numérique Auteurs : R. N. WICKRAMASEKARA, Auteur ; B. ROBERTSON, Auteur ; J. HULEN, Auteur ; J. HALLGREN, Auteur ; H. A. F. STESSMAN, Auteur Article en page(s) : p.1554-1571 Langues : Anglais (eng) Mots-clés : Adult  Animals  Anxiety/genetics  Autism Spectrum Disorder/genetics  Disease Models, Animal  Fear  Female  Grooming  Humans  Male  Mice  Mice, Knockout  Social Behavior  Young Adult  genetics  genotype-phenotype correlation  mouse models Index. décimale : PER Périodiques Résumé : Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD. En ligne : http://dx.doi.org/10.1002/aur.2516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449 [article] Differential effects by sex with Kmt5b loss [Texte imprimé et/ou numérique] / R. N. WICKRAMASEKARA, Auteur ; B. ROBERTSON, Auteur ; J. HULEN, Auteur ; J. HALLGREN, Auteur ; H. A. F. STESSMAN, Auteur . - p.1554-1571. Langues : Anglais (eng) in Autism Research > 14-8 (August 2021) . - p.1554-1571 Mots-clés : Adult  Animals  Anxiety/genetics  Autism Spectrum Disorder/genetics  Disease Models, Animal  Fear  Female  Grooming  Humans  Male  Mice  Mice, Knockout  Social Behavior  Young Adult  genetics  genotype-phenotype correlation  mouse models Index. décimale : PER Périodiques Résumé : Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD. En ligne : http://dx.doi.org/10.1002/aur.2516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449

Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism / C. M. HUDAC in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.24 Titre : Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism Type de document : Texte imprimé et/ou numérique Auteurs : C. M. HUDAC, Auteur ; H. A. F. STESSMAN, Auteur ; Trent D. DESCHAMPS, Auteur ; A. KRESSE, Auteur ; S. FAJA, Auteur ; E. NEUHAUS, Auteur ; S. J. WEBB, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur Article en page(s) : p.24 Langues : Anglais (eng) Mots-clés : Autism spectrum disorders (ASD)  Electroencephalography (EEG)  Likely gene-disrupting mutations  Molecular subtyping  Mu rhythm attenuation  Social cognition  Social perception Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Promising initiatives utilizing interdisciplinary characterization of ASD suggest phenotypic subtypes related to specific likely gene-disrupting mutations (LGDMs). However, the role of functionally associated LGDMs in the neural social phenotype is unknown. METHODS: In this study of 26 children with ASD (n = 13 with an LGDM) and 13 control children, we characterized patterns of mu attenuation and habituation as children watched videos containing social and nonsocial motions during electroencephalography acquisition. RESULTS: Diagnostic comparisons were consistent with prior work suggesting aberrant mu attenuation in ASD within the upper mu band (10-12 Hz), but typical patterns within the lower mu band (8-10 Hz). Preliminary exploration indicated distinct social sensitization patterns (i.e., increasing mu attenuation for social motion) for children with an LGDM that is primarily expressed during embryonic development. In contrast, children with an LGDM primarily expressed post-embryonic development exhibited stable typical patterns of lower mu attenuation. Neural social indices were associated with social responsiveness, but not cognition. CONCLUSIONS: These findings suggest unique neurophysiological profiles for certain genetic etiologies of ASD, further clarifying possible genetic functional subtypes of ASD and providing insight into mechanisms for targeted treatment approaches. En ligne : http://dx.doi.org/10.1186/s11689-017-9199-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350 [article] Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism [Texte imprimé et/ou numérique] / C. M. HUDAC, Auteur ; H. A. F. STESSMAN, Auteur ; Trent D. DESCHAMPS, Auteur ; A. KRESSE, Auteur ; S. FAJA, Auteur ; E. NEUHAUS, Auteur ; S. J. WEBB, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur . - p.24. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.24 Mots-clés : Autism spectrum disorders (ASD)  Electroencephalography (EEG)  Likely gene-disrupting mutations  Molecular subtyping  Mu rhythm attenuation  Social cognition  Social perception Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous disorder. Promising initiatives utilizing interdisciplinary characterization of ASD suggest phenotypic subtypes related to specific likely gene-disrupting mutations (LGDMs). However, the role of functionally associated LGDMs in the neural social phenotype is unknown. METHODS: In this study of 26 children with ASD (n = 13 with an LGDM) and 13 control children, we characterized patterns of mu attenuation and habituation as children watched videos containing social and nonsocial motions during electroencephalography acquisition. RESULTS: Diagnostic comparisons were consistent with prior work suggesting aberrant mu attenuation in ASD within the upper mu band (10-12 Hz), but typical patterns within the lower mu band (8-10 Hz). Preliminary exploration indicated distinct social sensitization patterns (i.e., increasing mu attenuation for social motion) for children with an LGDM that is primarily expressed during embryonic development. In contrast, children with an LGDM primarily expressed post-embryonic development exhibited stable typical patterns of lower mu attenuation. Neural social indices were associated with social responsiveness, but not cognition. CONCLUSIONS: These findings suggest unique neurophysiological profiles for certain genetic etiologies of ASD, further clarifying possible genetic functional subtypes of ASD and providing insight into mechanisms for targeted treatment approaches. En ligne : http://dx.doi.org/10.1186/s11689-017-9199-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350

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