Current Developments in the Genetics of Autism: From Phenome to Genome

Losh, Molly; Sullivan, Patrick F.; Trembath, Dimitri G.; Piven, Joseph

doi:10.1097/nen.0b013e318184482d

Cited by 94 publications

(88 citation statements)

References 143 publications

(94 reference statements)

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“…Heritability of common risk alleles in multiplex families also is reflected in behavioral profiles in parents of children with ASD. Thus, the broader autism phenotype is found to a far greater extent in parents from multiplex compared with simplex families (28,29), suggesting that heritable, rather than de novo mechanisms for ASD expression occur in multiplex families. Collectively, there seem to be a number of different genetic etiologies that can contribute to altering MET signaling in many individuals with ASD.…”

Section: Figurementioning

confidence: 99%

“…Private (de novo) functional mutations also impart genetic risk. Analyses suggest that, at the genetic and behavioral levels, multiplex families may be fundamentally different from simplex families (24,(26)(27)(28)(29). Furthermore, multiple genes or even multiple mutations of the same gene may be involved in the etiology of the same clinically diagnosed disorder in different individuals.…”

Section: Distinct Patterns Of Heritability Of Risk Alleles In Asdmentioning

confidence: 99%

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The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

2009

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Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.Autism spectrum disorder (ASD) is a syndrome characterized by a triad of core deficits: disturbances in social behavior, atypical verbal and nonverbal communication, and restricted interests that can be accompanied by repetitive behavior. The clinical diagnosis, which includes individuals with any one of a spectrum of neurodevelopmental conditions (including autism, Rett syndrome, pervasive developmental disorder-not otherwise specified, and Asperger syndrome), is made in 1 of every 150 individuals and is four times more prevalent in boys than girls (1). While ASD is among the most heritable psychiatric disorders defined in the Diagnostic and statistical manual of mental disorders (4th edition) (2), it is not a static or simple disorder with fixed effects on a circumscribed age. Instead, equally fundamental facets of pathology emerge at different points of maturation of the child. Moreover, the disorder does not result in immutable social and cognitive deficits, but rather the core symptoms typically change over time and to different degrees. Co-occurring medical conditions (sleep problems, epilepsy, and gastrointestinal symptoms) and psychiatric disturbances (anxiety, obsessive-compulsive disorder, and aggression) are common and can appear at different ages in children on the spectrum.Contemporary hypotheses of the causes of ASD often include experience-dependent processes through which atypical gene-by-environment (G X E) interactions yield pathophysiology in later emerging systems that underlie social and communication competencies. The later emergence of symptoms is consistent with the concept that developmental differentiation, whether at the cellular, circuit, or systems level, occurs from the bottom up; behavior develops from basic sensory and perceptual systems that feed into higher integration centers (3-5). Impairments in initial basic processes become expressed in ever more complex systems, with the population heterogeneity of the clinical features of ASD expected to increase from infancy to childhood and through adolescence. However, it is not clear whether the factors that contribute to the developmental diversification and phenotypic heterogeneity of...

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Section: Figurementioning

confidence: 99%

Section: Distinct Patterns Of Heritability Of Risk Alleles In Asdmentioning

confidence: 99%

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

2009

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“…Indeed, in 2010, we do not know how many different disorders are embedded in the current diagnosis of schizophrenia or autism or other current categories that share clinical features. Our expectation, based on experience in cancer, heart disease, and infectious diseases, is that identifying syndromes based on pathophysiology will eventually be able to improve outcomes (e.g., 7,8).…”

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confidence: 99%

Research Domain Criteria (RDoC): Toward a New Classification Framework for Research on Mental Disorders

Insel¹,

Cuthbert²,

Garvey³

et al. 2010

AJP

5,751

185

4,136

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“…1 The gender ratio is highly skewed, with ϳ80% of affected individuals being male. There is strong evidence that genetic factors play a critical role in vulnerability to ASD, 2 with heritability estimates from twin studies as high as 90%. 3 Moreover, there have been recent advances in identifying specific genetic causes of ASD, such as genomic copy-number variants in genes involved in synaptic cell adhesion and related pathways, which have been identified in as many as 7% to 10% of people with ASD.…”

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confidence: 99%

Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study

et al. 2011

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WHAT'S KNOWN ON THIS SUBJECT:The sibling recurrence risk of autism has been estimated to be between 3% and 10%. Previous research was affected by small samples and selection, stoppage, and reporting limitations. Updated estimates of recurrence risk are needed. WHAT THIS STUDY ADDS:Studying a large sample and using a prospective longitudinal design, this study demonstrated that the sibling recurrence risk of autism spectrum disorder is substantially higher than previous estimates. This elevated risk has important implications for infant screening and genetic counseling. abstract OBJECTIVE: The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD. METHODS:A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n ϭ 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician. RESULTS:A total of 18.7% of the infants developed ASD. Infant gender and the presence of Ͼ1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was Ͼ1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome. CONCLUSIONS:The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed. Pediatrics 2011;128:e488-e495 AUTHORS:

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Current Developments in the Genetics of Autism: From Phenome to Genome

Cited by 94 publications

References 143 publications

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

Research Domain Criteria (RDoC): Toward a New Classification Framework for Research on Mental Disorders

Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study

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