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30. Characterization of Idiopathic Autism and 22q11.2 Syndromic Forms of Autism
Biological Psychiatry
Thursday Abstracts
idiopathic risk populations. A growing literature focuses on 22q11.2 Deletion Syndrome (22q11DS), a neurogenetic syndrome associated with 25% risk for psychosis in youth. Prospective harmonized studies in idiopathic and neurogenetic groups can elucidate mechanisms underlying emergence of psychosis. Methods: We examined subthreshold psychotic features, psychopathology and cognition in three large samples: Nondeleted psychosis spectrum (ND-PS) and typically developing (TD) from the Philadelphia Neurodevelopmental Cohort, and molecularly confirmed 22q11DS. Participants were assessed for subthreshold psychotic symptoms with the Structured Interview for Prodromal Symptoms (SIPS) and for psychopathology with a computerized K-SADS. The Penn Computerized Neurocognitive Battery (CNB) provided performance measures on the following domains: Executive, Episodic Memory, Complex Cognition, Social Cognition, Sensorimotor. A subsample was followed over 24 years. Results: Comorbidity among psychiatric conditions was common in ND-PS and 22q11DS as it unfolds developmentally. The pattern of subthreshold psychotic features was similar. Cognition was more impaired in 22q11DS with greater developmental delay. Social and complex cognition were selectively impaired in both groups. Persistence and worsening of psychosis symptoms related to higher negative symptoms at intake and poorer functioning. Conclusions: Features of psychosis risk are similar in idiopathic and neurogenetic samples with increased risk for schizophrenia spectrum disorders. While cognitive deficits are more pronounced in the neurogenetic sample, the similar pattern of cognitive deficits and evolution of positive and negative symptoms supports the notion of an identifiable mechanistic pathway to psychosis. Supported By: NIMH Keywords: Early psychosis, Neurocognition, Neurogenetics, 22q11 Deletion Syndrome, Neurodevelopment
30. Characterization of Idiopathic Autism and 22q11.2 Syndromic Forms of Autism Robert Schultz1, Caitlin Clements2, Judith Miller3, Ashley de Marchena3, Elaine Zackai3, Beverly Emanuel3, Donna McDonald-McGinn3, and Tara Wenger4 1
University of Pennsylvania & Center for Autism Research, Children’s Hospital of Philadelphia, 2University of Pennsylvania, 3Children’s Hospital of Philadelphia, 4 Seattle Children’s Hospital Background: While 22q11.2 Deletion Syndrome (22q11.2DS) is associated with autism, less is known about autism risk in 22q11.2 Duplication Syndrome (22q11.2DupS). Moreover, it is not known which of the 30-40 genes in this region confer autism risk. We compared adaptive functioning, psychiatric symptoms and autism rates in individuals with 22q11.2DupS, 22q11.2DS, idiopathic autism, typically developing controls (TDCs), and in those with atypical 22q11.2 CNVs. Methods: Participants matched on age and sex included 22q11.2DupS (n528), 22q11.2DS (n562), ASD (n570), and
TDCs (n573). In addition, 36 individuals with atypical duplications (n59) or deletions (n527) of the 22q11.2 region were included. Early social communication skills, psychiatric symptoms, and cognitive and adaptive functioning at 6, 12 and 24 months were evaluated in a separate group of 210 infants at risk for autism. Results: Individuals with 22q11.2DupS had elevated rates of autism (25%). Both the 22q11.2DupS and 22q11.2DS groups showed greater impairment than the TDC group on all social and adaptive functioning indices. A significantly higher rate of ASD diagnoses (38.4%) was observed for individuals with the proximal 22q11.2 DupS and DS than the distal 22q11.2 cases (8.7%). Atypical motor development is evident in autism at 6 months of age and by 12 months there is significant decline in adaptive and cognitive functioning and increased ASD features. Conclusions: 22q11.2DupS and DS show increased ASD risk and impairments in adaptive and social functions. The proximal 22q11.2 region, harboring COMT and RANBP1, confers higher risk for ASD than distal regions. Study of idiopathic ASD shows impairments starting at age 6 months. Supported By: Simons Foundation Keywords: Autism Spectrum Disorder, 22q11.2 CNV, Human, development, atypical CNV
31. Deciphering the Molecular Mechanisms Underlying the 16p11.2 Syndromes using Rodent Models Sandra Martin Lorenzo, Thomas Arbogast, and Yann Herault IGBMC, CNRS, INSERM, Université de Strasbourg Background: A large number of copy number variations (CNVs) have been associated with genomic disorders. The 16p11.2 deletion and duplication syndromes are part of those CNV syndromes with rearrangement affecting a 600Kb conserved region with 29 genes and a population prevalence of each approximately 1/2000. Symptoms indicate that 16p11.2 deletion and duplication have opposite effects on morphology, metabolism and brain function with the deletion associated with autism spectrum disorder (ASD) and the duplication with ASD and schizophrenia. Methods: To identify dosage-sensitive gene(s) whose expression changes lead to the antagonistic phenotypes, we generated new mouse models for the deletion and duplication of the 16p11.2 homologous region and characterized the mouse models using an exhaustive series of behavioral and metabolic tests. We additionally explored the contribution of two different genetic contexts, additional parameters and single candidate genes to phenotypes. Results: Overall, alterations of genetic dosage of the 16p11 region recapitulated human behavioral phenotypes in activity and memory in mice, but the metabolic defects were opposite in the two species. Conclusions: The dosage imbalance at the 16p11.2 locus interacts with modifiers outside the CNV to determine the penetrance, expressivity and direction of effects in both humans and mice. We are currently using new rodent models of candidate genes to identify the major genetic driver for the 16p11.2 CNV syndromes.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S13
Thursday Abstracts
idiopathic risk populations. A growing literature focuses on 22q11.2 Deletion Syndrome (22q11DS), a neurogenetic syndrome associated with 25% risk for psychosis in youth. Prospective harmonized studies in idiopathic and neurogenetic groups can elucidate mechanisms underlying emergence of psychosis. Methods: We examined subthreshold psychotic features, psychopathology and cognition in three large samples: Nondeleted psychosis spectrum (ND-PS) and typically developing (TD) from the Philadelphia Neurodevelopmental Cohort, and molecularly confirmed 22q11DS. Participants were assessed for subthreshold psychotic symptoms with the Structured Interview for Prodromal Symptoms (SIPS) and for psychopathology with a computerized K-SADS. The Penn Computerized Neurocognitive Battery (CNB) provided performance measures on the following domains: Executive, Episodic Memory, Complex Cognition, Social Cognition, Sensorimotor. A subsample was followed over 24 years. Results: Comorbidity among psychiatric conditions was common in ND-PS and 22q11DS as it unfolds developmentally. The pattern of subthreshold psychotic features was similar. Cognition was more impaired in 22q11DS with greater developmental delay. Social and complex cognition were selectively impaired in both groups. Persistence and worsening of psychosis symptoms related to higher negative symptoms at intake and poorer functioning. Conclusions: Features of psychosis risk are similar in idiopathic and neurogenetic samples with increased risk for schizophrenia spectrum disorders. While cognitive deficits are more pronounced in the neurogenetic sample, the similar pattern of cognitive deficits and evolution of positive and negative symptoms supports the notion of an identifiable mechanistic pathway to psychosis. Supported By: NIMH Keywords: Early psychosis, Neurocognition, Neurogenetics, 22q11 Deletion Syndrome, Neurodevelopment
30. Characterization of Idiopathic Autism and 22q11.2 Syndromic Forms of Autism Robert Schultz1, Caitlin Clements2, Judith Miller3, Ashley de Marchena3, Elaine Zackai3, Beverly Emanuel3, Donna McDonald-McGinn3, and Tara Wenger4 1
University of Pennsylvania & Center for Autism Research, Children’s Hospital of Philadelphia, 2University of Pennsylvania, 3Children’s Hospital of Philadelphia, 4 Seattle Children’s Hospital Background: While 22q11.2 Deletion Syndrome (22q11.2DS) is associated with autism, less is known about autism risk in 22q11.2 Duplication Syndrome (22q11.2DupS). Moreover, it is not known which of the 30-40 genes in this region confer autism risk. We compared adaptive functioning, psychiatric symptoms and autism rates in individuals with 22q11.2DupS, 22q11.2DS, idiopathic autism, typically developing controls (TDCs), and in those with atypical 22q11.2 CNVs. Methods: Participants matched on age and sex included 22q11.2DupS (n528), 22q11.2DS (n562), ASD (n570), and
TDCs (n573). In addition, 36 individuals with atypical duplications (n59) or deletions (n527) of the 22q11.2 region were included. Early social communication skills, psychiatric symptoms, and cognitive and adaptive functioning at 6, 12 and 24 months were evaluated in a separate group of 210 infants at risk for autism. Results: Individuals with 22q11.2DupS had elevated rates of autism (25%). Both the 22q11.2DupS and 22q11.2DS groups showed greater impairment than the TDC group on all social and adaptive functioning indices. A significantly higher rate of ASD diagnoses (38.4%) was observed for individuals with the proximal 22q11.2 DupS and DS than the distal 22q11.2 cases (8.7%). Atypical motor development is evident in autism at 6 months of age and by 12 months there is significant decline in adaptive and cognitive functioning and increased ASD features. Conclusions: 22q11.2DupS and DS show increased ASD risk and impairments in adaptive and social functions. The proximal 22q11.2 region, harboring COMT and RANBP1, confers higher risk for ASD than distal regions. Study of idiopathic ASD shows impairments starting at age 6 months. Supported By: Simons Foundation Keywords: Autism Spectrum Disorder, 22q11.2 CNV, Human, development, atypical CNV
31. Deciphering the Molecular Mechanisms Underlying the 16p11.2 Syndromes using Rodent Models Sandra Martin Lorenzo, Thomas Arbogast, and Yann Herault IGBMC, CNRS, INSERM, Université de Strasbourg Background: A large number of copy number variations (CNVs) have been associated with genomic disorders. The 16p11.2 deletion and duplication syndromes are part of those CNV syndromes with rearrangement affecting a 600Kb conserved region with 29 genes and a population prevalence of each approximately 1/2000. Symptoms indicate that 16p11.2 deletion and duplication have opposite effects on morphology, metabolism and brain function with the deletion associated with autism spectrum disorder (ASD) and the duplication with ASD and schizophrenia. Methods: To identify dosage-sensitive gene(s) whose expression changes lead to the antagonistic phenotypes, we generated new mouse models for the deletion and duplication of the 16p11.2 homologous region and characterized the mouse models using an exhaustive series of behavioral and metabolic tests. We additionally explored the contribution of two different genetic contexts, additional parameters and single candidate genes to phenotypes. Results: Overall, alterations of genetic dosage of the 16p11 region recapitulated human behavioral phenotypes in activity and memory in mice, but the metabolic defects were opposite in the two species. Conclusions: The dosage imbalance at the 16p11.2 locus interacts with modifiers outside the CNV to determine the penetrance, expressivity and direction of effects in both humans and mice. We are currently using new rodent models of candidate genes to identify the major genetic driver for the 16p11.2 CNV syndromes.
Biological Psychiatry May 15, 2017; 81:S1–S139 www.sobp.org/journal
S13