Autism traits in the RASopathies

• Published in: Journal of medical genetics Vol. 51; no. 1; pp. 10 - 20
• Main Authors: Adviento, Brigid, Corbin, Iris L, Widjaja, Felicia, Desachy, Guillaume, Enrique, Nicole, Rosser, Tena, Risi, Susan, Marco, Elysa J, Hendren, Robert L, Bearden, Carrie E, Rauen, Katherine A, Weiss, Lauren A
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.01.2014
• Subjects: Adolescent; Adult; Autism; Autistic Disorder - diagnosis; Autistic Disorder - genetics; Cell cycle; Child; Costello Syndrome - diagnosis; Costello Syndrome - genetics; Diagnosis, Differential; Ectodermal Dysplasia - diagnosis; Ectodermal Dysplasia - genetics; Facies; Failure to Thrive - diagnosis; Failure to Thrive - genetics; Female; Genes; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; Humans; Kinases; Male; Middle Aged; Mitogen-Activated Protein Kinases - metabolism; Mutation; Neuropsychological Tests; Noonan Syndrome - diagnosis; Noonan Syndrome - genetics; Patient Outcome Assessment; Phenotype; Prevalence; Proteins; Quantitative Trait, Heritable; ras Proteins - genetics; ras Proteins - metabolism; Sex Factors; Siblings; Signal Transduction; Surveys and Questionnaires; Young Adult; United States > US; California; Autism; Cranio-Facio-Cutaneous Syndrome; Noonan Syndrome; Costello Syndrome; Neurofibromatosis Type 1
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2013-101951

Background 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. Methods 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). Results 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. Conclusions 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.