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EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction / A. DE BOER in Molecular Autism, 9 (2018)
[article]
Titre : EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction Type de document : Texte imprimé et/ou numérique Auteurs : A. DE BOER, Auteur ; K. VERMEULEN, Auteur ; J. I. M. EGGER, Auteur ; J. G. E. JANZING, Auteur ; N. DE LEEUW, Auteur ; H. E. VEENSTRA-KNOL, Auteur ; N. S. DEN HOLLANDER, Auteur ; H. VAN BOKHOVEN, Auteur ; W. STAAL, Auteur ; T. 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
in Molecular Autism > 9 (2018) . - 5p.[article] EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction [Texte imprimé et/ou numérique] / A. DE BOER, Auteur ; K. VERMEULEN, Auteur ; J. I. M. EGGER, Auteur ; J. G. E. JANZING, Auteur ; N. DE LEEUW, Auteur ; H. E. VEENSTRA-KNOL, Auteur ; N. S. DEN HOLLANDER, Auteur ; H. VAN BOKHOVEN, Auteur ; W. STAAL, Auteur ; T. 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 Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features / E. K. BAKER in Molecular Autism, 10 (2019)
[article]
Titre : Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features Type de document : Texte imprimé et/ou numérique Auteurs : E. K. BAKER, Auteur ; M. ARPONE, Auteur ; S. M. ALIAGA, Auteur ; L. BRETHERTON, Auteur ; C. M. KRAAN, Auteur ; M. BUI, Auteur ; H. R. SLATER, Auteur ; L. LING, Auteur ; D. FRANCIS, Auteur ; M. F. HUNTER, Auteur ; J. ELLIOTT, Auteur ; C. ROGERS, Auteur ; M. FIELD, Auteur ; J. COHEN, Auteur ; Kim CORNISH, Auteur ; L. SANTA MARIA, Auteur ; V. FAUNDES, Auteur ; B. CUROTTO, Auteur ; P. MORALES, Auteur ; C. TRIGO, Auteur ; I. SALAS, Auteur ; A. M. ALLIENDE, Auteur ; D. J. AMOR, Auteur ; D. E. GODLER, Auteur Article en page(s) : 21 p. Langues : Anglais (eng) Mots-clés : Autism FMR1 mRNA Fragile X syndrome Intellectual disability Mosaicism Index. décimale : PER Périodiques Résumé : Background: Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: >/= 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS. Methods: The study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method. Results: Females with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group. Conclusion: Incomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS. En ligne : http://dx.doi.org/10.1186/s13229-019-0271-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=398
in Molecular Autism > 10 (2019) . - 21 p.[article] Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features [Texte imprimé et/ou numérique] / E. K. BAKER, Auteur ; M. ARPONE, Auteur ; S. M. ALIAGA, Auteur ; L. BRETHERTON, Auteur ; C. M. KRAAN, Auteur ; M. BUI, Auteur ; H. R. SLATER, Auteur ; L. LING, Auteur ; D. FRANCIS, Auteur ; M. F. HUNTER, Auteur ; J. ELLIOTT, Auteur ; C. ROGERS, Auteur ; M. FIELD, Auteur ; J. COHEN, Auteur ; Kim CORNISH, Auteur ; L. SANTA MARIA, Auteur ; V. FAUNDES, Auteur ; B. CUROTTO, Auteur ; P. MORALES, Auteur ; C. TRIGO, Auteur ; I. SALAS, Auteur ; A. M. ALLIENDE, Auteur ; D. J. AMOR, Auteur ; D. E. GODLER, Auteur . - 21 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 21 p.
Mots-clés : Autism FMR1 mRNA Fragile X syndrome Intellectual disability Mosaicism Index. décimale : PER Périodiques Résumé : Background: Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: >/= 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS. Methods: The study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method. Results: Females with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group. Conclusion: Incomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS. En ligne : http://dx.doi.org/10.1186/s13229-019-0271-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=398