Abstract
Dysregulation of the Ras MAPK signaling pathway is implicated in the pathogenesis of autism spectrum disorder (ASD). The RASopathies, a group of disorders caused by mutations of the Ras/MAPK pathway genes, share many overlapping clinical features. Studies suggest a high prevalence of ASD in the RASopathies, but detailed characterization of the ASD profile is lacking. The aim of this study was to compare the ASD symptom profile of three distinct RASopathies associated with both gain-of-function and loss-of-function mutations: neurofibromatosis type 1 (NF1), Noonan syndrome (NS), and cardiofaciocutaneous syndrome (CFC). Participants were drawn from existing databases if they had a diagnosis of a RASopathy, met the criteria for ASD, and were able to communicate verbally. We compared the phenotypic profile of NF1 + ASD (n = 48), NS + ASD (n = 11), and CFC + ASD (n = 7) on the Autism Diagnostic Inventory (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). We found subtle but non-significant group differences with higher levels of social impairments and lower restricted repetitive behaviors in the NF1 group as compared with the NS and CFC groups. We observed group differences in developmental milestones with most severe delays in CFC, followed by NS and NF1. Our results suggest that despite developmental differences, the ASD profile remains relatively consistent across the three RASopathies. Though our results need confirmation in larger samples, they suggest the possibility that treatment and mechanistic insights developed in the context of one RASopathy may be generalizable to others and possibly to non-syndromic ASD associated with dysregulation of Ras/MAPK pathway genes.
Highlights
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication, restricted repetitive behaviors, and sensory sensitivities
Regression of skills, which is a common feature in autism, was not reported in cardiofaciocutaneous syndrome (CFC) but reported by 6.4% of parents in the Noonan syndrome (NS) group and 9.1% in the neurofibromatosis 1 (NF1) group. This is the first study to compare the developmental and core ASD symptom profiles in children with RASopathies and ASD. In this cross-syndrome study, our results suggest subtle but non-significant differences in ASD symptom profiles with higher reciprocal social communication impairments but lower levels of restricted repetitive behaviors in the NF1 group as compared with the NS and CFC groups
In two large cohorts of non-syndromic ASD, the mean Comparative Severity Score (CSS) on the Autism Diagnostic Observation Schedule (ADOS) social affect and RRB were comparable with the RASopathies in this study
Summary
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication, restricted repetitive behaviors, and sensory sensitivities. Hundreds of genes are implicated in ASD, studies using systems biology approaches suggest that these genes converge on a parsimonious set of downstream molecular pathways that are important for human brain development [2]. Many of these downstream pathways are important for regulating protein synthesis, synaptic plasticity, and chromatic remodeling [3,4,5]. More recent studies have implicated an important mechanistic link between ASD and the mitogen activated protein kinase (MAPK) signaling pathway which has a key role in regulating synaptic plasticity and memory [4, 6]. The MAPK pathway is well known for its role in oncogenesis and is critically involved in the regulation of the cell cycle [7], but its role in neurodevelopment is becoming clear [8,9,10]
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