Clinical phenotype of ASD-associated DYRK1A haploinsufficiency / Rachel K. EARL in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 54p. Titre : Clinical phenotype of ASD-associated DYRK1A haploinsufficiency Type de document : texte imprimé Auteurs : Rachel K. EARL, Auteur ; Tychele N. TURNER, Auteur ; Heather C. MEFFORD, Auteur ; Caitlin M. HUDAC, Auteur ; Jennifer GERDTS, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur Article en page(s) : 54p. Langues : Anglais (eng) Mots-clés : Autism  Clinical phenotype  Dyrk1a  Disruptive mutation  Genetic syndrome  Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Clinical phenotype of ASD-associated DYRK1A haploinsufficiency [texte imprimé] / Rachel K. EARL, Auteur ; Tychele N. TURNER, Auteur ; Heather C. MEFFORD, Auteur ; Caitlin M. HUDAC, Auteur ; Jennifer GERDTS, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur . - 54p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 54p. Mots-clés : Autism  Clinical phenotype  Dyrk1a  Disruptive mutation  Genetic syndrome  Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk / Anne B. ARNETT in Journal of Child Psychology and Psychiatry, 59-3 (March 2018)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 59-3 (March 2018) . - p.268-276 Titre : Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk Type de document : texte imprimé Auteurs : Anne B. ARNETT, Auteur ; Brianna E. CAIRNEY, Auteur ; Arianne S. WALLACE, Auteur ; Jennifer GERDTS, Auteur ; Tychele N. TURNER, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur Article en page(s) : p.268-276 Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : https://doi.org/10.1111/jcpp.12815 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=339 [article] Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk [texte imprimé] / Anne B. ARNETT, Auteur ; Brianna E. CAIRNEY, Auteur ; Arianne S. WALLACE, Auteur ; Jennifer GERDTS, Auteur ; Tychele N. TURNER, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur . - p.268-276. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 59-3 (March 2018) . - p.268-276 Index. décimale : PER Périodiques En ligne : https://doi.org/10.1111/jcpp.12815 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=339

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk / Natasha MARRUS in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk Type de document : texte imprimé Auteurs : Natasha MARRUS, Auteur ; Tychele N. TURNER, Auteur ; Elizabeth FORSEN, Auteur ; Drew BOLSTER, Auteur ; Alison MARVIN, Auteur ; Andrew WHITEHOUSE, Auteur ; Laura KLINGER, Auteur ; Christina A. GURNETT, Auteur ; J.N. CONSTANTINO, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/epidemiology/genetics  Autistic Disorder/epidemiology/genetics  Genetic Counseling  Humans  Parents  Prospective Studies  Early detection  Family studies  Personalized medicine  Reproductive health planning  for the Social Responsiveness Scale. Index. décimale : PER Périodiques Résumé : BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. METHODS: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. RESULTS: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. CONCLUSIONS: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study. En ligne : https://dx.doi.org/10.1186/s11689-021-09389-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk [texte imprimé] / Natasha MARRUS, Auteur ; Tychele N. TURNER, Auteur ; Elizabeth FORSEN, Auteur ; Drew BOLSTER, Auteur ; Alison MARVIN, Auteur ; Andrew WHITEHOUSE, Auteur ; Laura KLINGER, Auteur ; Christina A. GURNETT, Auteur ; J.N. CONSTANTINO, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Autism Spectrum Disorder/epidemiology/genetics  Autistic Disorder/epidemiology/genetics  Genetic Counseling  Humans  Parents  Prospective Studies  Early detection  Family studies  Personalized medicine  Reproductive health planning  for the Social Responsiveness Scale. Index. décimale : PER Périodiques Résumé : BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. METHODS: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. RESULTS: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power-with the exception of isolated rare inherited pathogenic variants -does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. CONCLUSIONS: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study. En ligne : https://dx.doi.org/10.1186/s11689-021-09389-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

The autism spectrum phenotype in ADNP syndrome / Anne B. ARNETT in Autism Research, 11-9 (September 2018)  

Public ISBD [article]  inAutism Research > 11-9 (September 2018) . - p.1300-1310 Titre : The autism spectrum phenotype in ADNP syndrome Type de document : texte imprimé Auteurs : Anne B. ARNETT, Auteur ; Candace L. RHOADS, Auteur ; Kendra HOEKZEMA, Auteur ; Tychele N. TURNER, Auteur ; Jennifer GERDTS, Auteur ; Arianne S. WALLACE, Auteur ; Sandra BEDROSIAN-SERMONE, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur Article en page(s) : p.1300-1310 Langues : Anglais (eng) Mots-clés : Adnp  autism spectrum disorder  developmental disorder  genetic syndrome  intellectual disability Index. décimale : PER Périodiques Résumé : Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment. En ligne : http://dx.doi.org/10.1002/aur.1980 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369 [article] The autism spectrum phenotype in ADNP syndrome [texte imprimé] / Anne B. ARNETT, Auteur ; Candace L. RHOADS, Auteur ; Kendra HOEKZEMA, Auteur ; Tychele N. TURNER, Auteur ; Jennifer GERDTS, Auteur ; Arianne S. WALLACE, Auteur ; Sandra BEDROSIAN-SERMONE, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur . - p.1300-1310. Langues : Anglais (eng) in Autism Research > 11-9 (September 2018) . - p.1300-1310 Mots-clés : Adnp  autism spectrum disorder  developmental disorder  genetic syndrome  intellectual disability Index. décimale : PER Périodiques Résumé : Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. Autism Res 2018, 11: 1300-1310. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment. En ligne : http://dx.doi.org/10.1002/aur.1980 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369

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