Autism genetics: searching for specificity and convergence

Berg, Jamee M; Geschwind, Daniel H.

doi:10.1186/gb-2012-13-7-247

Cited by 170 publications

(138 citation statements)

References 146 publications

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“…Autism spectrum disorders are often framed as the outcome of aberrant development and interconnectivity of brain structures (Berg and Geschwind, 2012; Courchesne et al, 2001; Geschwind and Levitt, 2007). This prompts the question of whether ideas about dysfunctional homeostasis in ASD might be applicable to neurodevelopment.…”

Section: Development Boxmentioning

confidence: 99%

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Mullins

Fishell

Tsien

2016

Neuron

166

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Understanding the mechanisms underlying autism spectrum disorders (ASD) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops, and provide detailed commentary for exemplar genes within each module.

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Section: Development Boxmentioning

confidence: 99%

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Mullins

Fishell

Tsien

2016

Neuron

166

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“…The broad range of cognitive and behavioral profiles seen in diagnosed ASDs has been long viewed as a challenge by the research community (4). Although it is well established that (i) the cognitive/behavioral profile of people diagnosed with ASDs varies widely and (ii) the set of genetic factors related to ASDs varies widely (5,6), the degree to which phenotype can be used to predict patterns in disease architecture remains unclear.…”

mentioning

confidence: 99%

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Robinson

Samocha

Kosmicki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

134

118

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Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.neuropsychiatric genetics | epidemiology | heterogeneity | phenotype

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“…Recent studies suggest that at least 1000 genes contribute to the disorder, with a combination of common variants of small to moderate effect and rare variants with potential larger effect sizes. 6,7 Common single nucleotide polymorphisms (SNPs) that act in an additive manner are estimated to explain about 17% of the variance in liability to ASD, whereas copy number variants explain approximately 10% of the autism phenotype. [8][9][10] Exome and genome sequencing studies have provided strong evidence for the involvement of rare variants in autism, suggesting novel candidate genes in the disorder.…”

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability

et al. 2015

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Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P = 6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P = 0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P = 7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P = 0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P = 0.003, permP = 0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder. INTRODUCTIONAutism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by impairments in reciprocal social interaction, verbal and non-verbal communication and stereotyped patterns of behavior. The prevalence for ASD is estimated to be about 0.5-1%, and it is approximately four times more frequent in males than in females. [1][2][3] Family and twin studies in recent decades have provided strong evidence showing that ASD is one of the most heritable neuropsychiatric disorders. Sibling recurrence risk is approximately 20%, and concordance among twins may range from 76 to 88% for monozygotic twins and from 0 to 31% for dizygotic twins, depending on phenotypic criteria. 4,5 The genetic model for idiopathic autism is complex. Recent studies suggest that at least 1000 genes contribute to the disorder, with a combination of common variants of small to moderate effect and rare variants with potential larger effect sizes. 6,7

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Autism genetics: searching for specificity and convergence

Abstract: Advances in genetics and genomics have improved our understanding of autism spectrum disorders. As many genes have been implicated, we look to points of convergence among these genes across biological systems to better understand and treat these disorders.

Cited by 170 publications

References 146 publications

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability

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