EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction / Anneke DE BOER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 5p. Titre : EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction Type de document : texte imprimé Auteurs : Anneke DE BOER, Auteur ; Karlijn VERMEULEN, Auteur ; Jos EGGER, Auteur ; Joost G.E. JANZING, Auteur ; Nicole DE LEEUW, Auteur ; Hermine E. VEENSTRA-KNOL, Auteur ; Nicolette S. DEN HOLLANDER, Auteur ; Hans VAN BOKHOVEN, Auteur ; Wouter STAAL, Auteur ; Tjitske KLEEFSTRA, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Cognition  Ehtm1  Kleefstra syndrome  Major depressive disorder  Mosaicism Index. décimale : PER Périodiques Résumé : Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism. Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects. Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects. Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population. En ligne : http://dx.doi.org/10.1186/s13229-018-0193-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction [texte imprimé] / Anneke DE BOER, Auteur ; Karlijn VERMEULEN, Auteur ; Jos EGGER, Auteur ; Joost G.E. JANZING, Auteur ; Nicole DE LEEUW, Auteur ; Hermine E. VEENSTRA-KNOL, Auteur ; Nicolette S. DEN HOLLANDER, Auteur ; Hans VAN BOKHOVEN, Auteur ; Wouter STAAL, Auteur ; Tjitske KLEEFSTRA, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 5p. Mots-clés : Autism spectrum disorder  Cognition  Ehtm1  Kleefstra syndrome  Major depressive disorder  Mosaicism Index. décimale : PER Périodiques Résumé : Background: Genetic mosaicism is only detected occasionally when there are no obvious health or developmental issues. Most cases concern healthy parents in whom mosaicism is identified upon targeted testing of a genetic defect that was initially detected in their children. A germline genetic defect affecting the euchromatin histone methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, which is associated with the typical triad of distinct facial appearance, (childhood) hypotonia, and intellectual disability. A high degree of psychopathology is associated with this syndrome. A few parents with a mosaic EHMT1 mutation have been detected upon testing after a child was diagnosed with a germline EHMT1 defect. At first glance, carriers of a mosaic EHMT1 mutation appeared to function normally. However, recent studies have shown that de novo, postzygotic mutations in important developmental genes significantly contribute to autism spectrum disorder (ASD). Therefore, we hypothesized that EHMT1 mosaicism could cause neuropsychiatric defects. To investigate this, we performed a detailed investigation of cognitive neuropsychiatric parameters in parents identified with EHMT1 mosaicism. Methods: Three adults (two males, one female) with a genetically confirmed diagnosis of EHMT1 mosaicism were examined by means of a battery of tests and observational instruments covering both neurocognitive and psychiatric features. The battery included the following instruments: the Autism Diagnostic Observation Schedule (ADOS), the mini Psychiatric Assessment Schedules for Adults with Developmental Disabilities (mini PAS-ADD), the Vineland Adaptive Behavior Scales (VABS), and the Cambridge Neuropsychological Test Automated Battery (CANTAB). These measures were compared with our previously reported data from Kleefstra syndrome patients with confirmed (germline) EHMT1 defects. Results: All three subjects achieved maximum total scores on the VABS, indicative of adequate (adaptive) functioning. In all, scores above cutoff were found on the ADOS for ASD and on the mini PAS-ADD for major depressive disorder (lifetime). Finally, results on the CANTAB showed impaired cognitive flexibility in all subjects. Conclusion: Individuals with EHMT1 mosaicism seem to have increased vulnerability for developing severe psychopathology, especially ASD and mood disorders. Although at first glance they appear to be well-adapted in their daily functioning, they may experience significant psychiatric symptoms and show reduced cognitive flexibility in comparison to the general population. En ligne : http://dx.doi.org/10.1186/s13229-018-0193-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

From man to fly - convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes / Benjamin HARICH in Journal of Child Psychology and Psychiatry, 61-5 (May 2020)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 61-5 (May 2020) . - p.545-555 Titre : From man to fly - convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes Type de document : texte imprimé Auteurs : Benjamin HARICH, Auteur ; Marieke KLEIN, Auteur ; Charlotte W. OCKELOEN, Auteur ; Monique VAN DER VOET, Auteur ; Marlies SCHIMMEL-NABER, Auteur ; Nicole DE LEEUW, Auteur ; Annette SCHENCK, Auteur ; Barbara FRANKE, Auteur Article en page(s) : p.545-555 Langues : Anglais (eng) Mots-clés : Drosophila melanogaster  Fbxo25  Tdrp  Adhd  psychiatric comorbidities Index. décimale : PER Périodiques Résumé : BACKGROUND: Mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD), have a complex etiology, and identification of underlying genetic risk factors is challenging. This study used a multistep approach to identify and validate a novel risk gene for ADHD and psychiatric comorbidity. METHODS: In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copy-number variations (CNVs) linked to disease. Genes present in the identified CNV were subsequently tested for their association with ADHD in the largest data set currently available (n = 55,374); this gene-set and gene-based association analyses were based on common genetic variants. Significant findings were taken forward for functional validation using Drosophila melanogaster as biological model system, altering gene expression using the GAL4-UAS system and a pan-neuronal driver, and subsequently characterizing locomotor activity and sleep as functional readouts. RESULTS: We identified a copy number gain in 8p23.3, which segregated with psychiatric phenotypes in the family and was confirmed by quantitative RT-PCR. Common genetic variants in this locus were associated with ADHD, especially those in FBXO25 and TDRP. Overexpression of the FBXO25 orthologue in two Drosophila models consistently led to increased locomotor activity and reduced sleep compared with the genetic background control. CONCLUSIONS: We combine ADHD risk gene identification in an individual family with genetic association testing in a large case-control data set and functional validation in a model system, together providing an important illustration of an integrative approach suggesting that FBXO25 contributes to key features of ADHD and comorbid neuropsychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13161 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=422 [article] From man to fly - convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes [texte imprimé] / Benjamin HARICH, Auteur ; Marieke KLEIN, Auteur ; Charlotte W. OCKELOEN, Auteur ; Monique VAN DER VOET, Auteur ; Marlies SCHIMMEL-NABER, Auteur ; Nicole DE LEEUW, Auteur ; Annette SCHENCK, Auteur ; Barbara FRANKE, Auteur . - p.545-555. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 61-5 (May 2020) . - p.545-555 Mots-clés : Drosophila melanogaster  Fbxo25  Tdrp  Adhd  psychiatric comorbidities Index. décimale : PER Périodiques Résumé : BACKGROUND: Mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD), have a complex etiology, and identification of underlying genetic risk factors is challenging. This study used a multistep approach to identify and validate a novel risk gene for ADHD and psychiatric comorbidity. METHODS: In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copy-number variations (CNVs) linked to disease. Genes present in the identified CNV were subsequently tested for their association with ADHD in the largest data set currently available (n = 55,374); this gene-set and gene-based association analyses were based on common genetic variants. Significant findings were taken forward for functional validation using Drosophila melanogaster as biological model system, altering gene expression using the GAL4-UAS system and a pan-neuronal driver, and subsequently characterizing locomotor activity and sleep as functional readouts. RESULTS: We identified a copy number gain in 8p23.3, which segregated with psychiatric phenotypes in the family and was confirmed by quantitative RT-PCR. Common genetic variants in this locus were associated with ADHD, especially those in FBXO25 and TDRP. Overexpression of the FBXO25 orthologue in two Drosophila models consistently led to increased locomotor activity and reduced sleep compared with the genetic background control. CONCLUSIONS: We combine ADHD risk gene identification in an individual family with genetic association testing in a large case-control data set and functional validation in a model system, together providing an important illustration of an integrative approach suggesting that FBXO25 contributes to key features of ADHD and comorbid neuropsychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13161 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=422

LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions / Helle LYBÆK in Autism Research, 15-3 (March 2022)  

Public ISBD [article]  inAutism Research > 15-3 (March 2022) . - p.421-433 Titre : LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions Type de document : texte imprimé Auteurs : Helle LYBÆK, Auteur ; Michael ROBSON, Auteur ; Nicole DE LEEUW, Auteur ; Jayne Y. HEHIR-KWA, Auteur ; Aaron JEFFRIES, Auteur ; Bjørn Ivar HAUKANES, Auteur ; Siren BERLAND, Auteur ; Diederik DE BRUIJN, Auteur ; Stefan MUNDLOS, Auteur ; Malte SPIELMANN, Auteur ; Gunnar HOUGE, Auteur Article en page(s) : p.421-433 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p?< 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20% 26% lower than expected from Hardy?Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. Lay Summary LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females. En ligne : https://doi.org/10.1002/aur.2677 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions [texte imprimé] / Helle LYBÆK, Auteur ; Michael ROBSON, Auteur ; Nicole DE LEEUW, Auteur ; Jayne Y. HEHIR-KWA, Auteur ; Aaron JEFFRIES, Auteur ; Bjørn Ivar HAUKANES, Auteur ; Siren BERLAND, Auteur ; Diederik DE BRUIJN, Auteur ; Stefan MUNDLOS, Auteur ; Malte SPIELMANN, Auteur ; Gunnar HOUGE, Auteur . - p.421-433. Langues : Anglais (eng) in Autism Research > 15-3 (March 2022) . - p.421-433 Index. décimale : PER Périodiques Résumé : Abstract LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p?< 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20% 26% lower than expected from Hardy?Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. Lay Summary LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females. En ligne : https://doi.org/10.1002/aur.2677 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

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