The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors

Fischbach, Gerald D.; Lord, Catherine

doi:10.1016/j.neuron.2010.10.006

Cited by 658 publications

(658 citation statements)

References 11 publications

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“…This study uses data from the Simons Simplex Collection (SSC), a deeply phenotyped sample of more than 2,800 individuals with ASDs and their families (33). The SSC includes only simplex cases of ASD, defined through the lack of another affected family member as close or closer than first cousins.…”

Section: Methodsmentioning

confidence: 99%

“…The family history analyses controlled for proband race/ethnicity (white non-Hispanic, black Non-Hispanic, Asian, Hispanic, other) which has been linked to variation in psychiatric disease prevalence and reporting (43). Although the broad autism phenotype (BAP) could also in principle be used to examine variation in ASD familiality (44, 45), we did not include BAP or autistic trait measures in the analysis because suspected ASD in family members (which could be indexed by a high concentration of autistic traits) was used as an SSC exclusion criterion (33). Last, we also examined the relationship between LOF rate and other variables in the sequenced subset-including language development, behavioral severity, and proband seizure history-controlling for proband full-scale IQ in each analysis.…”

Section: Methodsmentioning

confidence: 99%

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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.

136

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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

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.

136

118

View full text Add to dashboard Cite

show abstract

“…The first set is derived from nearly 5,000 parents in a collection of families with only one child on the autism spectrum, the SSC (15). Obviously, some of these parents may be carriers of variation contributing to ASD, so statistics extracted from these families may overestimate the rare variation seen in candidate autism genes.…”

Section: Sources Of Human Sequence Variation From Whole-exome Sequencementioning

confidence: 99%

“…They apply their particular tolerance score on targets from a subset of the Simons Simplex Collection (SSC), a collection of simplex autism families (5,7,8,15). More recently, additional evidence has been shown for transmission of mutations in genes with low tolerance using the RVIS from mothers (16).…”

mentioning

confidence: 99%

Low load for disruptive mutations in autism genes and their biased transmission

Iossifov

Levy

Allen

et al. 2015

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

146

150

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We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in wholeexome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.autism spectrum disorder | gene vulnerability | disruptive mutations | biased transmission | autism genes T he past decade has seen remarkable progress in understanding genetic causation of autism spectrum disorders (ASD), confirmatory of predictions made by a "unified" genetic theory of autism proposed in 2007 (1). This theory proposes that much of ASD is caused by new mutation, sometimes directly contributing to the disorder through germ-line mutation, or transmitted by parents, especially females, who carry a variant of recent vintage without experiencing severe consequences. The theory was based largely on three sets of observations: (i) low ASD incidence in females compared with males (2), (ii) apparently dominant transmission to male children in multiplex families (1), and (iii) greater incidence of de novo (DN) copy number mutation in children with ASD than in their siblings in simplex families (3, 4). Since then, evidence for causal DN mutation has accumulated (5-8). These damaging mutations generally affect only one allele, suggesting that gene targets are dosage-sensitive, prone to dominant negative mutation, or some combination of these factors.A widely held genetic model for autism is that combinations of common variation are the major driving force. As we argue, there is little evidence for this belief. Damaging DN mutation contributes to at least 30% of ASD in simplex families (9). Among such damaging mutations are those mutations that are likely gene-disruptive (LGD) in that they create nonsense, splice-site, or small frame-shift variants (5). The estimates of contribution from DN mutations derive from the statistical...

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“…This is due, in part, to the rarity of specific CNVs limiting sample sizes, and also because of differing ascertainment approaches, rendering equivalent comparisons impossible. The detailed characterization of , LeeAnne Green Snyder, PhD 6,10 , Sarah Spence, MD 11 , Melissa B. Ramocki, MD 12 , David W. Evans, PhD 13 , John E. Spiro, PhD 10 , Christa L. Martin, PhD 13,14 , David H. Ledbetter, PhD 13,14 and Wendy K. Chung, MD 15,16 ; on behalf of the Simons VIP consortium.…”

Section: Introductionmentioning

confidence: 99%

Clinical phenotype of the recurrent 1q21.1 copy-number variant

Bernier

Steinman

Reilly

et al. 2016

Genetics in Medicine

144

163

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Purpose:To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. Methods:Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.Results: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.Conclusions: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.

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The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors

Cited by 658 publications

References 11 publications

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

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

Low load for disruptive mutations in autism genes and their biased transmission

Clinical phenotype of the recurrent 1q21.1 copy-number variant

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