Autism traits in the RASopathies

Department of Psychiatry, University of California San Francisco, San Francisco, California, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 10/2013; 51(1). DOI: 10.1136/jmedgenet-2013-101951
Source: PubMed


Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

Download full-text


Available from: Robert L Hendren, Dec 17, 2013
  • Source
    • "This is likely attributable to disrupted cell proliferation and differentiation due to mutation of the neurofibromin protein [Lee et al., 2010]. This finding is notable given that early brain overgrowth is one of the earliest signs of autism [Courchesne et al., 2003], which is present at elevated rates in individuals with NF1 and other disorders involving mutations in the Ras/MAPK signaling pathway [ " Ras-opathies " ; Adviento et al., 2014]. Some studies have attributed this enlargement in NF1 individuals to globally increased white matter volume [Dubovsky et al., 2001; Margariti et al., 2007]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 08/2015; DOI:10.1002/hbm.22937 · 5.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: When embryological development of the internal and/or external genitalia is disrupted, the patient presents with a disorder of sex development (DSD) in the neonatal period or sometime later in life. Some of these patients have other, nongenital malformations, which makes their overall management more complex than if they just had a DSD. This Review summarises these malformation syndromes and discusses the recent research into their aetiology. The genetic causes of these malformation syndromes, when they are known, will also be described. Many specific genetic mutations are now known in malformation syndromes with a defect in hormonal function. By contrast, the genetic causes remain unknown in many nonhormonal morphological anomalies that affect the genitalia.
    Nature Reviews Endocrinology 06/2014; 10(8). DOI:10.1038/nrendo.2014.83 · 13.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Autism spectrum disorder (ASD) is reported to be increased in neurofibromatosis type 1 (NF1), but it's unknown if ASD screening tools are sensitive and specific for NF1. This study compared the rate at which children with NF1 screen-positive for two ASD screening tools [Modified Checklist for Autism in Toddlers (M-CHAT) and Childhood Autism Spectrum Test (CAST)] to the screen-positive rate of the general population. A retrospective cross-sectional observational design to investigate the association between children with NF1 and at risk status for ASD was used. Medical records of children between 16 months and 11 years of age seen in an NF Clinic were reviewed for an ASD screening questionnaire. There were no statistically significant differences in the screen-positive rate for ASD in NF1 compared to published controls, but mean CAST scores were higher in NF1. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2014; 164(7). DOI:10.1002/ajmg.a.36549 · 2.16 Impact Factor
Show more