Altered canonical and striatal-frontal resting state functional connectivity in children with pathogenic variants in the Ras/mitogen-activated protein kinase pathway

Abstract

Mounting evidence supports the role of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway in neurodevelopmental disorders. Here, the authors used a genetics-first approach to examine how Ras/MAPK pathogenic variants affect the functional organization of the brain and cognitive phenotypes including weaknesses in attention and inhibition. Functional MRI was used to examine resting state functional connectivity (RSFC) in association with Ras/MAPK pathogenic variants in children with Noonan syndrome (NS). Participants (age 4–12 years) included 39 children with NS (mean age 8.44, SD=2.20, 25 females) and 49 typically developing (TD) children (mean age 9.02, SD=9.02, 33 females). Twenty-eight children in the NS group and 46 in the TD group had usable MRI data and were included in final analyses. The results indicated significant hyperconnectivity for the NS group within canonical visual, ventral attention, left frontoparietal and limbic networks (p<0.05 FWE). Higher connectivity within canonical left frontoparietal and limbic networks positively correlated with cognitive function within the NS but not the TD group. Further, the NS group demonstrated significant group differences in seed-based striatal-frontal connectivity (Z>2.6, p<0.05 FWE). Hyperconnectivity within canonical brain networks may represent an intermediary phenotype between Ras/MAPK pathogenic variants and cognitive phenotypes, including weaknesses in attention and inhibition. Altered striatal-frontal connectivity corresponds with smaller striatal volume and altered white matter connectivity previously documented in children with NS. These results may indicate delayed maturation and compensatory mechanisms and they are important for understanding the pathophysiology underlying cognitive phenotypes in NS and in the broader population of children with neurodevelopmental disorders.

Neuropsychiatric phenotypes in children with Noonan syndrome

“…Interestingly, deficits in emotion regulation processing in children with idiopathic ADHD have been linked to altered development of the striato‐amygdalo‐medial prefrontal cortical network, 40 which is known to be impacted in children with Noonan syndrome and PTPN11 pathogenic variants 17 . Children with Noonan syndrome also demonstrate hyperconnectivity within striatal‐frontal networks in comparison with typically developing children, 15 indicating that children with Noonan syndrome may be at increased risk for dysfunction within these pathways that contribute to difficulties with emotion regulation.…”

“…Informed consent was provided by the parent or guardian of all participants, with assent given by participants over age 7 years, as approved by the institutional review board of Stanford University (IRB #3192). A subset of the 45 children with Noonan syndrome described in the present paper were also included in previous work from our group ( n = 39 in Bruno et al, 15 n = 17 in Fattah et al, 16 n = 12 in Johnson et al 17 ). Detailed recruitment and exclusion criteria are presented in Appendix S1.…”

A familial modeling framework for advancing precision medicine in neuropsychiatric disorders: A study in children with RASopathies

“…Gene discovery has also demonstrated that the encoded proteins of varied genes involved with ASD and other neuropsychiatric disorder cluster within the Ras/MAPK signaling pathway suggesting that these disorders are associated with enrichment of Ras/MAPK signaling [21,22]. Finally, NS significantly impacts brain development resulting in altered brain structure [23][24][25] and functional connectivity [26].…”

“…Moreover, NS has a large effect on neurobiological development [23,24,26], which may represent an important intermediate phenotype (i.e. endophenotype) between Ras/MAPK pathogenic variants and neuropsychiatric phenotypes (Fig 1b .).…”