Phenotypic Profile of Children with ASD with Gene Disruptions in the Beta-Catenin Pathway

Background:   Autism spectrum disorder (ASD) is a genotypically and phenotypically complex disorder. Gene disruptions within the beta-catenin pathway have been associated with ASD (O’Roak et al, 2012). Beta-catenin plays a critical biological role in cell growth and differentiation, and is believed to be involved in synaptic formation as well as memory and learning processes (Maguschak & Ressler, 2012). Understanding the phenotypic profile that accompanies genetic mutations in this specific pathway can help to tease apart potential ASD subtypes that arise from different genetic disruptions. 

Objectives:  To explore the cognitive and behavioral phenotype as well as gender distribution of individuals with ASD who have a gene disruption in the beta-catenin pathway compared to affected individuals without this pathway mutation.

Methods:  Participants were 2557 children meeting strict criteria for ASD. 94 children (29 female) with disruptive mutations falling in a protein network within the beta-catenin pathway were compared to 2151 children (312 female) without gene disrupting mutations in this network. Groups were compared on nonverbal (NVIQ) and verbal IQ (VIQ), as well as parent-reported and clinician-observed measures of social impairment and repetitive behaviors as a function of gender.

Results:   Groups differed in gender rate, with a higher rate of females in the beta-catenin pathway group than the non-pathway group (c²(1, N=2557) = 25.9, p<.001). Children in the pathway group had lower nonverbal and verbal IQ scores relative to the non-pathway group (NVIQ: F(1,2552) = 21.7, p<.001, η²=.008; VIQ: F(1,2552) = 6.56, p=.010, η²=.003). There was an interaction between pathway status and gender, indicating a trend toward increased social impairment in males in the pathway group and no differences in females across groups (F(1,2421)=4.19, p=.041, η²=.002).

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Conclusions:  Higher rates of females in the beta-catenin pathway group replicate previous findings of higher incidence of genetic mutations and copy number variations in females with ASD (Marshall et al, 2008). The phenotype of children with beta-catenin pathway disruption is characterized by significantly greater cognitive impairment and increased social impairment in males, echoing beta-catenin’s role in memory, learning, and socioaffective processes. Phenotypic subtyping such as this is a promising way to illuminate genotypic variations amongst individuals with ASD.