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

This large study looked at brain-related conditions in people with Noonan syndrome, a genetic condition. They found much higher rates than in the general population: 31% had ADHD, 23% had intellectual disability, 11% had autism, 9% had epilepsy, and 23% had depression or anxiety. This shows that children with Noonan syndrome need regular screening for these conditions so they can get early support and treatment.

This systematic review and meta-analysis examined the prevalence of neurodevelopmental and psychiatric conditions in individuals with Noonan syndrome, a genetic disorder affecting the RAS/MAPK signalling pathway. Analyzing 20-21 studies, researchers found significantly elevated rates of brain-related disorders compared to the general population: intellectual developmental disorder (23%), ADHD (31%), autism spectrum disorder (11%), epilepsy (9%), and depression/anxiety (23%). The findings demonstrate that Noonan syndrome is strongly associated with multiple neurodevelopmental conditions, highlighting the need for systematic screening and monitoring in this population. However, limited genotype-specific data prevents understanding of how different genetic variants may influence disorder prevalence.

Results support implementing systematic neurodevelopmental screening protocols for children with Noonan syndrome. Early identification enables timely intervention for ADHD, autism, intellectual disability, and mental health conditions. Regular monitoring throughout development is warranted given the high prevalence of multiple comorbid conditions.

Limited genotype-specific data prevents understanding of how different genetic variants influence disorder prevalence. Sample sizes and study methodologies of included studies not specified. Heterogeneity between studies may affect precision of prevalence estimates.

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.