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Cognitive and behavioural genetics
Original article
Autism traits in the RASopathies
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  1. Brigid Adviento1,2,
  2. Iris L Corbin1,2,3,
  3. Felicia Widjaja1,
  4. Guillaume Desachy1,2,
  5. Nicole Enrique4,
  6. Tena Rosser5,
  7. Susan Risi1,
  8. Elysa J Marco6,
  9. Robert L Hendren1,
  10. Carrie E Bearden4,7,
  11. Katherine A Rauen2,8,
  12. Lauren A Weiss1,2
  1. 1Department of Psychiatry, University of California San Francisco, San Francisco, California, USA
  2. 2Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
  3. 3Prenatal Diagnosis Center, Sutter Pacific Medical Foundation, San Francisco, California, USA
  4. 4Department of Psychology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA
  5. 5Department of Neurology, Children's Hospital Los Angeles, Los Angeles, California, USA
  6. 6Department of Child Neurology, University of California San Francisco, San Francisco, California, USA
  7. 7Department of Psychology, University of California Los Angeles, Los Angeles, California, USA
  8. 8Department of Pediatrics Genetics, University of California San Francisco, San Francisco, California, USA
  1. Correspondence to Dr Lauren A Weiss, Department of Psychiatry, Institute for Human Genetics, Center for Neurobiology and Psychiatry, Langley Porter Psychiatric Institute, Nina Ireland Lab, Box F-0984, 401 Parnassus Avenue, Rm. A101, San Francisco, CA 94143-0984, USA; Lauren.Weiss{at}ucsf.edu

Abstract

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.

  • Autism
  • Neurofibromatosis Type 1
  • Costello Syndrome
  • Noonan Syndrome
  • Cranio-Facio-Cutaneous Syndrome

https://doi.org/10.1136/jmedgenet-2013-101951

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