Journal Article

Genotype–phenotype correlations with autism spectrum disorder-related traits in Noonan syndrome and Noonan syndrome with multiple lentigines: a cross-sectional study

Fuhrmann, Naomi, Pannone, Luca, Russo, Odeya, Martinelli, Simone, McGhee, Chloe Alexa, Plank, Julia R., Radio, Francesca Clementina, Tartaglia, Marco, Green, Tamar, Ruggeri, Aurora

2025

Overview

Background Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. Methods This study included 121 individuals with NS ( PTPN11 : 88, SOS1 : 18, RAF1 : 6, KRAS : 2, RIT1 : 3, NRAS : 2, LZTR1 : 2, SOS2 : 1) and seven individuals with NSML ( PTPN11 ), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11 -associated NS variants examined genotype–phenotype relationships. Results Compared to TD individuals, those with PTPN11 -associated NS, NSML, and SOS1 -associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11 -associated NS and NSML exhibited greater ASD-related challenges than those with RAF1 . Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11 -associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype–phenotype links. Limitations Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. Conclusions This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11 -associated NS and NSML compared to other variants. Additionally, individuals with PTPN11 -associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11 -associated NS, this study may inform future targeted treatment approaches.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Adult / Age / Analysis / Autism / Autism Spectrum Disorder - genetics / Behavior / Care and treatment / Child / Child, Preschool / Complications and side effects / Cross-Sectional Studies / Diagnosis / Emotional regulation / Female / Females / Genes / Genetic aspects / Genetic Association Studies / Genotype / Genotype & phenotype / Genotype-phenotype correlations / Human Genetics / Humans / Investigations / Kinases / LEOPARD Syndrome - complications / LEOPARD Syndrome - genetics / Male / Medicine / Medicine & Public Health / Neurology / Neuropsychology / Neurosciences / Noonan syndrome / Noonan Syndrome - complications / Noonan Syndrome - genetics / Noonan syndrome with multiple lentigines / Pediatrics / Phenotype / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics / Proteins / Psychiatry / PTPN11 / RASopathies / Young Adult