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. 2021 Jan 15:11:585700.
doi: 10.3389/fpsyt.2020.585700. eCollection 2020.

Autism Spectrum Disorder Symptom Profile Across the RASopathies

Marie-Maude Geoffray  1   2 , Bruno Falissard  3 , Jonathan Green  2   4   5 , Browyn Kerr  4   6 , D Gareth Evans  2   4   7 , Susan Huson  4   6 , Emma Burkitt-Wright  4   6 , Shruti Garg  2   4   5
Affiliations

Autism Spectrum Disorder Symptom Profile Across the RASopathies

Marie-Maude Geoffray et al. Front Psychiatry. .

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.

Keywords: ASD; Noonan syndrome; RASopathies; cardio-facio-cutaneous syndrome; early intervention; neurofibromatosis type 1.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Current clinical profile with ADOS items (common across modules 2, 3, and 4) in the 3 RASopathies, CFC, Noonan Syndrome and NFl. Mean and Standard Error are represented for each item.
Figure 2
Figure 2
Clinical profile by the “4–5 most abnormal/ever” AD I-R subscores ADI-R subscores in the 3 RASopathies. Mean and Standard Error are presented for each subscores.
Figure 3
Figure 3
Age of acquisition early developmental milestones based on the parent structured interview of ADI in CFC, NS, and NFl.
See this image and copyright information in PMC

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