Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection

Davidson, Julie; Goin‐Kochel, Robin P.; Green-Snyder, Lee Anne; Hundley, Rachel; Warren, Zachary; Peters, Sarika U.

doi:10.1007/s10803-012-1492-1

Cited by 33 publications

(36 citation statements)

References 22 publications

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“…8 This suggests that a significant fraction of the underlying genetic etiology in the SSC might be inherited, a notion that has been examined previously. 17 Our study benefited from the quad-based design of the SSC, 18 which provided a robust genetic control for each ASD proband, as well as the detailed phenotypic information available, which sharpened the contrasts between severely affected and less affected probands and their siblings, some of which showed subtle signs of the BAP. 17 Most of our observations were strengthened or restricted to SRS-discordant quads, where the proband was severely affected in terms of the SRS scale but the sibling was unaffected.…”

Section: Discussionmentioning

confidence: 99%

“…17 Our study benefited from the quad-based design of the SSC, 18 which provided a robust genetic control for each ASD proband, as well as the detailed phenotypic information available, which sharpened the contrasts between severely affected and less affected probands and their siblings, some of which showed subtle signs of the BAP. 17 Most of our observations were strengthened or restricted to SRS-discordant quads, where the proband was severely affected in terms of the SRS scale but the sibling was unaffected. Approximately 67% (276/411) of the quads in this study were categorized as SRS discordant, and these quads explained virtually the entire CNV burden, encompassed the majority of brain-expressed genes, and strengthened the association with previously implicated disease genes.…”

Section: Discussionmentioning

confidence: 99%

“…15 In this study, we tested the hypothesis that small genic inherited CNVs also contribute to the genetic etiology of sporadic autism. Several lines of evidence-including increased prevalence of the broader autism phenotype (BAP) in parents of affected children, 16,17 trends for higher burden of extremely rare singly transmitted CNVs in simplex families, 1 and enrichment of large CNVs in cases versus unrelated controls 5 -are potentially supportive of this hypothesis. In contrast, other previous studies that examined inherited CNVs in ASD found no significant excess of inherited burden in probands with ASD, although these studies were mainly designed to detect de novo CNVs.…”

Section: Introductionmentioning

confidence: 99%

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Transmission Disequilibrium of Small CNVs in Simplex Autism

Krumm

O’Roak

Karakoç

et al. 2013

The American Journal of Human Genetics

105

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We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transmission Disequilibrium of Small CNVs in Simplex Autism

Krumm

O’Roak

Karakoç

et al. 2013

The American Journal of Human Genetics

105

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“…However, not all studies have reported such differences. Several investigations have documented increased expression of some (but not all) BAP features among male relatives using both family history (Szatmari et al, 2000, Bolton et al, 1994) as well as self/informant-report questionnaire methods (De la Marche et al, 2011, Davidson et al, 2012, Schwichtenberg et al, 2010). Of those studies employing direct assessment methods, elevated aloof, rigid, irritable and sensitive traits (Murphy et al, 2000) and increased pragmatic language features (Ruser et al, 2007, Dawson et al, 2007) have been detected among male relatives.…”

Section: Introductionmentioning

confidence: 99%

Sex differences and within-family associations in the broad autism phenotype

Klusek

Losh

Martin

2012

Autism

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While there is a strong sex bias in the presentation of autism, it is unknown whether this bias is also present in subclinical manifestations of autism among relatives, or the broad autism phenotype (BAP). This study examined this question, and investigated patterns of co-occurrence of BAP traits within families of individuals with autism. Pragmatic language and personality features of the BAP were studied in 42 fathers and 50 mothers of individuals with autism using direct assessment tools used in prior family studies of the BAP. Higher rates of aloof personality style were detected among fathers, while no sex differences were detected for other BAP traits. Within individuals, pragmatic language features were associated with the social personality styles of the BAP in mothers but not fathers. A number of BAP features were correlated within spousal pairs. Finally, associations were detected between paternal BAP characteristics and the severity of children’s autism symptoms in all three domains (social, communication, and repetitive behaviors). Mother-child correlations were detected for aspects of communication only. Together, findings suggest that most features of the BAP express comparably in males and females, and raise some specific questions about how such features might inform studies of the genetic basis of autism.

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“…For instance, Davidson et al (2014) [75] reported that frequency of BAP traits varies significantly depending upon the measure utilized, highlighting the need for a different approach that utilizes multiple informants and relies on the assessment of distinct BAP traits.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Evidence of Behavioral, Cognitive, and Psychiatric Endophenotypes in Autism: A Systematic Review

Ruparelia

Manji

Abubakar

et al. 2017

Autism Research and Treatment

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Substantial evidence indicates that parents of autistic individuals often display milder forms of autistic traits referred to as the broader autism phenotype (BAP). To determine if discrete endophenotypes of autism can be identified, we reviewed the literature to assess the evidence of behavioral, cognitive, and psychiatric profiles of the BAP. A systematic review was conducted using EMBASE, MEDLINE, PsycINFO, PsycEXTRA, and Global Health. Sixty papers met our inclusion criteria and results are discussed according to the proportion of studies that yield significant deficits per domain. The behavioral, cognitive, and psychiatric endophenotypes in parents of autistic probands are still not clarified; however, evidence suggests mild social/communication deficits, rigid/aloof personality traits, and pragmatic language difficulties as the most useful sociobehavioral candidate endophenotype traits. The existence of deficits in the cognitive domain does suggest familial vulnerability for autism. Furthermore, increased depressed mood and anxiety can also be useful markers; however, findings should be interpreted with caution because of the small number of studies in such heterogeneously broad domains and several methodological limitations.

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Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection

Cited by 33 publications

References 22 publications

Transmission Disequilibrium of Small CNVs in Simplex Autism

Transmission Disequilibrium of Small CNVs in Simplex Autism

Sex differences and within-family associations in the broad autism phenotype

Investigating the Evidence of Behavioral, Cognitive, and Psychiatric Endophenotypes in Autism: A Systematic Review

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