Social behavior in RASopathies and idiopathic autism

Foy, Allison M. H.; Hudock, Rebekah L.; Shanley, Ryan; Pierpont, Elizabeth I.

doi:10.1186/s11689-021-09414-w

Cited by 3 publications

(3 citation statements)

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“…Attention deficit, psychosocial and behavioral abnormalities are often associated, but there is no particular syndrome of behavioral disability or psychopathology observed in RASopathies. A wide spectrum of abnormalities has been reported including emotional dysregulation, irritability, and anxiety, obsessive–compulsive disorder, autism, or autistic traits (Alfieri et al, 2014; Foy, Hudock, Shanley, & Pierpont, 2022). Epilepsy of variable type and severity may occur.…”

Section: Shared Patterns Of Organ Involvement In Ns‐like Rasopathiesmentioning

confidence: 99%

Clinical overview on RASopathies

Zenker

2022

American J of Med Genetics Pt C

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RASopathies comprise a group of clinically overlapping developmental disorders caused by genetic variations affecting components or modulators of the RAS-MAPK signaling cascade, which lead to dysregulation of signal flow through this pathway. Noonan syndrome and the less frequent, clinically related disorders, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan syndrome-like disorder with loose anagen hair are part of the RASopathy spectrum and share a recognizable pattern of multisystem involvement. This review describes the "Noonan syndrome-like" phenotype as a common phenotypic signature of generalized developmental RAS pathway dysregulation. Distinctive features of the different entities are revisited against the background of the understanding of underlying genetic alterations and genotype correlations, which has evolved rapidly during the past 20 years, thereby leading to suggestions regarding the nosology of RASopathies. K E Y W O R D S cardiofaciocutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair 1 | INTRODUCTION The term "RASopathies" was coined in 2009 (Tidyman & Rauen, 2009). It denotes a group of clinically overlapping multisystem disorders that share a common molecular pathogenesis in that the underlying genetic variations affect components or modulators of the RAS-MAPK signaling cascade and lead to dysregulation of signal flow through this pathway. No generally accepted definition and definitive delineation of RASopathies exist, so far. The major classes of disorders that have been grouped under this umbrella term are summarized in Table 1. This clinical overview is focused on Noonan syndrome (NS; MIM #PS163950) and the less frequent, clinically related disorders, Costello syndrome (CS; MIM #218040), cardiofaciocutaneous syndrome (CFCS: MIM #PS115150), Noonan syndrome with multiple lentigines (NSML; MIM #151100), Noonan syndrome-like disorder with loose anagen hair (NSLH; MIM #PS607721), collectively referred to in the following as "Noonan syndrome-like RASopathies (NS-like RASopathies)." They represent disorders that are caused by a mild to moderate and generalized constitutional RAS pathway dysregulation (Figure 1a) and have a multisystem phenotype. Based on the current pathogenetic concepts and understanding it can be concluded that the "NS-like" clinical picture represents the common phenotypic signature of a systemic RAS pathway dysregulation that starts in the embryonic period. This notion is supported by the fact that all genes known to cause NS-like RASopathies encode for components or modulators of the RAS-MAPK signaling cascade. However, this does not mean that disturbed signaling through MAPKs as the sole effectors can explain all the organ-specific pathophysiology. In fact, cellular pathways are interconnected and abnormal signaling in one of them

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Section: Shared Patterns Of Organ Involvement In Ns‐like Rasopathiesmentioning

confidence: 99%

Clinical overview on RASopathies

Zenker

2022

American J of Med Genetics Pt C

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“…Foy et al. compared NF1, NS, CS, CFC, and iASD using the Social Emotional Assets and Resilience Scales (SEARS) and found social competence and empathy in RASopathy patients to be better than in iASD (Foy et al., 2022). For both RASopathies and iASD, the ratings for empathy were higher than for social competence, but in al the RASopathies this difference was significantly larger than in iASD.…”

Section: Resultsmentioning

confidence: 99%

Autism spectrum disorder profiles in RASopathies: A systematic review

Debbaut,

Steyaert,

El Bakkali

2024

Molec Gen & Gen Med

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BackgroundRASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually.MethodsWe conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers.ResultsWe included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio‐facio‐cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies.ConclusionsOur systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.

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“…Interestingly, ASD, which has a high prevalence in RASopathy patients, has similar symptomatic profile across the different syndromes regardless of developmental differences, suggesting a common underlying mechanistic link (Geoffray et al, 2020). When comparing children with the behaviourally defined, idiopathic ASD and children with RASopathies, the latter displayed more resilience in the domain of empathy relative to other social skills, as well as a negative association between emotional challenges and social competence (Foy et al, 2022). Although research of psycho-behavioural dysfunctions across the RASopathy spectrum is somewhat limited, generalised findings single out social impairments as common NPDrelated symptoms and further highlight anxiety-and depression-, and to a lesser extent, aggression-related problems occurring in patients with disordered RAS signalling (Walsh et al, 2020).…”

Section: Rasopathiesmentioning

confidence: 98%

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

Yotova

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Neurodevelopmental psychiatric disorders (NPDs) like attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia, affect millions of people worldwide. Despite recent progress in NPD research, much remains to be discovered about their underpinnings, therapeutic targets, effects of biological sex and age. Risk factors influencing brain development and signalling include prenatal inflammation and genetic variation. This dissertation aimed to build upon these findings by combining behavioural, molecular, and neuromorphological investigations in mouse models of such risk factors, i.e. maternal immune activation (MIA), neuron-specific overexpression (OE) of the cytoplasmatic isoforms of the RNA-binding protein RBFOX1, and neuronal deletion of the small Ras GTPase DIRAS2. Maternal infections during pregnancy pose an increased risk for NPDs in the offspring. While viral-like MIA has been previously established elsewhere, this study was the first in our institution to implement the model. I validated NPD-relevant deficits in anxiety- and depression-like behaviours, as well as dose- and sex-specific social deficits in mouse offspring following MIA in early gestation. Proteomic analyses in embryonic and adult hippocampal (HPC) synaptoneurosomes highlighted novel and known targets affected by MIA. Analysis of the embryonic dataset implicated neurodevelopmental disruptions of the lipid, polysaccharide, and glycoprotein metabolism, important for proper membrane function, signalling, and myelination, for NPD-pertinent sequelae. In adulthood, the observed changes encompassed transmembrane trafficking and intracellular signalling, apoptosis, and cytoskeletal organisation pathways. Importantly, 50 proteins altered by MIA in embryonic and adult HPC were enriched in the NPD-relevant synaptic vesicle cycle. A persistently upregulated protein cluster formed a functional network involved in presynaptic signalling and proteins downregulated in embryos but upregulated in adults by MIA were correlated with observed social deficits. 49/50 genes encoding these proteins were significantly associated with NPD- and comorbidity-relevant traits in human phenome-wise association study data for psychiatric phenotypes. These findings highlight NPD-relevant targets for future study and early intervention in at-risk individuals. MIA-evoked changes in the neuroarchitecture of the NPD-relevant HPC and prefrontal cortex (PFC) of male and female mice highlighted sex- and region-specific alterations in dendritic and spine morphology, possibly underlining behavioural phenotypes. To further investigate genetic risk factors of NPDs, I performed a study based on the implications of RBFOX1’s pleiotropic role in neuropsychiatric disorders and previous preclinical findings. Cytoplasmatic OE of RBFOX1, which affects the stability and translation of thousands of targets, was used to disseminate its role in morphology and behaviour. RBFOX1 OE affected dendritic length and branching in the male PFC and led to spine alterations in both PFC and HPC. Due to previously observed ASD-like endophenotypes in our Rbfox1 KO mice and the importance of gene × environment effects on NPD susceptibility, I probed the interaction of cytoplasmatic OE and a low-dose MIA on offspring. Both RBFOX1 OE alone and with MIA led to increased offspring loss during the perinatal period. Preliminary data suggested that RBFOX1 OE × MIA might increase anxiety- and anhedonia-like behaviours. Morphological changes in the adult male OE HPC and PFC suggested increased spine density and reduced dendritic complexity. A small post-mortem study in human dorsolateral PFC of older adults did not reveal significant effects of a common risk variant on RBFOX1 abundance. To expand upon NPD genetic risks, I evaluated the effects of a homo- (KO) or heterozygous (HET) Diras2 deletion in a novel, neuron-specific mouse model. DIRAS2’s function is largely unknown, but it has been associated with ADHD in humans and neurodevelopment in vitro. In adult mice, there were subtle sex-specific effects on behaviour, i.e. more pronounced NPD-relevant deficits in males, in keeping with human data. KO mice had subtly improved cognitive performance, while HET mice exhibited behaviours in line with core ADHD symptoms, e.g. earning difficulties (females), response inhibition deficits and hyperactivity (males), suggesting Diras2 dose-sensitivity and sex-specificity. The morphological findings revealed multiple aberrations in dendritic and spine morphology in the adult PFC, HPC, and amygdala of HET males. KOs changes in spine and dendritic morphology were exclusively in the PFC and largely opposite to those in HETs and NPD-like phenotypes. Region- and genotype-specific expression changes in Diras2 and Diras1 were observed in six relevant brain regions of adult HET and KO females, also revealing differences in the survival and morphology regulator mTOR, which might underlie observed differences. In conclusion, the effects of MIA and partial Diras2 knockdown resembled each other in core, NPD-associated behavioural and morphological phenotypes, while cytoplasmatic RBFOX1 OE and full Diras2 KO differed from those. My findings suggest complex dose- and sex-dependent relationships between these prenatal and genetic interventions, whose NPD-relevant influences might converge onto neurodevelopmental molecular pathways. An assessment of such putative overlap, based on available data from the MIA proteomic analyses of embryonic and adult HPC, suggested the three models might be linked via downstream targets, interactions, and upstream regulators. Future studies should disseminate both distinct and shared aspects of MIA, RBFOX1, and DIRAS2 relevant to NPDs and build upon these findings.

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Social behavior in RASopathies and idiopathic autism

Cited by 3 publications

References 105 publications

Clinical overview on RASopathies

Clinical overview on RASopathies

Autism spectrum disorder profiles in RASopathies: A systematic review

Translational study on the role of genetic and prenatal risk factors in neurodevelopmental psychiatric disorders

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