Prevalence of neurodevelopmental and psychiatric disorders in Noonan syndrome: a systematic review and meta-analysis

Noonan syndrome (NS) is a RASopathy, a group of genetic disorders caused by alterations in the RAS/MAPK signalling pathway, and is associated with brain-related disorders, including intellectual developmental disorder (IDD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), epilepsy, and depression and anxiety. However, estimates of prior prevalence vary widely. The aim of this systematic review and meta-analysis was to estimate the prevalence of brain-related disorders (i.e., IDD, ASD, ADHD, epilepsy, and depression and anxiety) in NS. A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted from inception to July 2025. Studies that estimated the prevalence of IDD, ASD, ADHD, epilepsy, and depression and anxiety in the population with NS were included. Genotype was considered when possible. Random-effects meta-analyses of prevalence, expressed as proportions (0-1) and their 95% confidence intervals (95% CI), were performed. Twenty-one studies were included in the systematic review, while 20 were included in the meta-analysis. The IDD prevalence was 0.23 (95% CI: 0.12, 0.35), the ASD prevalence was 0.11 (95% CI: 0.05, 0.17); the ADHD prevalence was 0.31 (95% CI: 0.22, 0.41); the epilepsy prevalence was 0.09 (95% CI: 0.03, 0.15) and the depression and anxiety prevalence was 0.23 (95% CI: 0.08, 0.39). There was hardly any genotype-specific data, particularly for minor mutations. NS is strongly associated with brain-related disorders, which reinforces the need for early and periodic screening in this population. Furthermore, genotype-phenotype correlation studies are required, as there is currently little evidence in this area. What is Known: • Noonan syndrome is a RASopathy characterised by short stature, heart disease and brain-related disorders. • Brain-related disorders include intellectual developmental disorder (IDD), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), among others. What is New: • IDD, ASD and ADHD were estimated to affect 23%, 11% and 31% of individuals, respectively. This is higher than the prevalence in the general population. • The prevalence of seizure disorders and emotional disorders was also high, although the evidence was more limited.