Autism traits in the RASopathies

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.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…22 Of note, germline variants in PTEN present the ASD, obesity, and macrocephaly triad of phenotypes, [66][67][68][69][70] whereas those in the Ras/MAPK signaling pathway are associated with social impairment. 71 The interactions observed at this cluster of genes, both at the chromatin and genetic level, suggest that the CNVprone non-overlapping loci at 16p11.2 should be approached and studied as ''connected regions'' rather than completely independent entities.…”

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…When evaluated clinically using DSM-IV-TR (American Psychiatric Association 2000) criteria, none of these children were found to meet diagnostic criteria for ASD. In another study by Adviento et al (2014), 21 % of participants with NS showed elevated ASD symptoms on the SCQ screening measure, which was significantly different than the rate of elevated scores found in a sibling comparison group (0 %). Scores on the Social Responsiveness Scale (SRS; Constantino and Gruber 2005), another screening measure of ASD symptoms, were also significantly higher in the NS group than the sibling group.…”

“…A number of studies have shown that mutations in genes acting more downstream in the RAS-MAPK pathway (e.g., BRAF, MEK 1, MEK2, HRAS), which typically cause CFC syndrome and Costello syndrome, tend to be associated with greater impairments in neurological, intellectual, and adaptive functioning than mutations in genes encoding components or regulators that act more upstream in the pathway (e.g., NF1, PTPN11, SOS1, RAF1), which cause NF1 and NS (Cesarini et al 2009;Pierpont et al 2010b;Yoon et al 2007). Individuals with gene mutations acting downstream in the pathway (especially those diagnosed with CFC syndrome) also tend to have a higher prevalence of autisticlike traits (Adviento et al 2014;Alfieri et al 2014).…”

“…Further, understanding the similarities and differences between NS and other distinct RASopathies (e.g., NF1) can also bring us to a better understanding of the variable clinical manifestations of RAS pathway anomalies. Only a handful of articles have evaluated individuals with multiple different RASopathies within the same study (e.g., Alfieri et al 2014;Adviento et al 2014;Pierpont et al 2010b;Cesarini et al 2009). This type of neuropsychological research can be challenging, as measures that are used to study one population may not easily be applied to other groups due to differences in phenotypic presentation and neurological involvement.…”

Social Competence in Children with Neurofibromatosis Type 1: Relationships with Psychopathology and Cognitive Ability

“…This is high compared to the rate of approximately 5% in the general population [20]. Children with NF1 also display a significantly higher prevalence of autism spectrum disorder (ASD) symptomatology compared to the general population, with three recent studies reporting that between 11% and 29% of children with NF1 are rated within the severe range on the Social Responsiveness Scale [21] (a screening measure of ASD symptomatology); a range which is strongly associated with a clinical diagnosis of ASD [6,22,23]. Importantly, however, NF1 is associated with impairments in several domains that overlap with ASD (including delayed social, executive, and language skills), and so the true prevalence of ASD in NF1 may be lower than these reports would indicate [24].…”