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Abstract
Autism spectrum disorders (ASDs) are characterized by deficits in three core behavioral domains: reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Several hundreds of risk genes for autism have been identified, however, it remains a challenge to associate these genes with specific core behavioral deficits. In multiplex autism families, affected sibs often show significant differences in severity of individual core phenotypes. We hypothesize that a higher mutation burden contributes to a larger difference in the severity of specific core phenotypes between affected sibs. We tested this hypothesis on social behavioral deficits in autism. We sequenced synaptome genes (n = 1,886) in affected male sib-pairs (n = 274) in families from the Autism Genetics Research Exchange (AGRE) and identified rare (MAF ≤ 1%) and predicted functional variants. We selected affected sib-pairs with a large (≥10; n = 92 pairs) or a small (≤4; n = 108 pairs) difference in total cumulative Autism Diagnostic Interview-Revised (ADI-R) social scores (SOCT_CS). We compared burdens of unshared variants present only in sibs with severe social deficits and found a higher burden in SOCT_CS≥10 compared to SOCT_CS ≤ 4 (SOCT_CS≥10: 705.1 ± 16.2; SOCT_CS ≤ 4, 668.3 ± 9.0; p = 0.025). Unshared SOCT_CS≥10 genes only in sibs with severe social deficits are significantly enriched in the SFARI gene set. Network analyses of these genes using InWeb_IM, molecular signatures database (MSigDB), and GeNetMeta identified enrichment for phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) (Enrichment Score [eScore] p value = 3.36E−07; n = 8 genes) and Nerve growth factor (NGF) (eScore p value = 8.94E−07; n = 9 genes) networks. These studies support a key role for these signaling networks in social behavioral deficits and present a novel approach to associate risk genes and signaling networks with core behavioral domains in autism.
Highlights
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders characterized by deficits in reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors
We identified an excess burden of rare deleterious variants in cohorts of sibs showing a large versus small differences in severity of social deficits defined by total cumulative Autism Diagnostic Interview-Revised (ADI-R) social interaction score (SOCT_CS)
We identified 274 affected male sib-pairs from multiplex families recruited to Autism Genetic Resource Exchange (AGRE)
Summary
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders characterized by deficits in reciprocal social interactions, communication, and restricted interests and/or repetitive behaviors. Case-control and family-based studies implicate risk alleles by identifying an association of common variants of small effect, a higher mutation load of rare variants of large effect, and/or presence of de novo variants in affected probands (De Rubeis and Buxbaum, 2015). Diagnosis of ASDs are based on standard, semi-quantitative behavioral tests including Autism Diagnostic Interview-Revised (ADI-R) (Lord et al, 1994) to assess deficits in three core behavioral domains: reciprocal social interaction, communication, and restricted interests and/or repetitive behaviors. Defects in all three domains are required to make a diagnosis, patients with ASDs often present with significant differences in the severity of specific behavioral domains Deficits in these behavioral domains are shared by other neuropsychiatric disorders. Due to extensive genetic heterogeneity and phenotypic variability (Jeste and Geschwind, 2014; De Rubeis and Buxbaum, 2015), it remains a major challenge to associate genetic risk genes and networks with specific behavioral domains in autism
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