Neurobehavioral Signatures in Overgrowth Intellectual Disability Syndromes: Dissecting Genotype-Phenotype Relationships in the PI3K-AKT-MTOR Pathway

Overgrowth intellectual disability syndromes (OGIDs) caused by mutations in the PI3K-AKT-MTOR pathway present significant neurobehavioral challenges. While PTEN Hamartoma Tumor Syndrome (PHTS) has been behaviorally characterized, Smith-Kingsmore Syndrome (SKS) has not, limiting our understanding of shared and unique features across OGIDs.

We conducted comprehensive neurobehavioral assessments in 17 individuals with SKS and compared them to previously characterized cohorts with PHTS (n=74), macrocephaly-associated autism (n=33), and healthy controls (n=32). Assessments included standardized measures of motor coordination, adaptive functioning, social interaction, and executive functioning. We performed genotype-phenotype correlation analyses and developed diagnostic classification models using recursive partitioning.

Individuals with SKS showed significant impairments across multiple domains compared to controls. Compared to the PTEN-ASD group, SKS individuals demonstrated particularly severe deficits in motor coordination and adaptive functioning, while executive functioning and behavioral regulation were similarly impaired. Novel clinical features were identified, including immune dysregulation and chronic constipation in SKS, and notably high rates of neonatal teeth (44.7%) in PHTS. Diagnostic classification models incorporating both behavioral and medical features achieved above-chance accuracy in distinguishing between conditions, with neonatal teeth emerging as a key distinguishing feature for PHTS. Domain-specific analyses showed variants in the PTEN phosphatase domain were associated with more severe social and executive function deficits compared to C2 domain variants. Correlation analyses between variant pathogenicity scores and clinical measures revealed limited consistent associations, though Combined Annotation Dependent Depletion (CADD) scores showed stable correlations with sensory processing measures across cohorts.

Our findings establish distinct neurobehavioral profiles between SKS and PHTS, suggesting different impacts of MTOR versus PTEN mutations on neural circuit development. The identification of novel phenotypic features expands the clinical spectrum of these disorders and provides new diagnostic markers. The limited predictive value of variant pathogenicity scores for neurobehavioral outcomes emphasizes the need for comprehensive individual assessments. These results provide a foundation for developing targeted interventions while highlighting the complexity of genotype-phenotype relationships in PI3K-AKT-MTOR pathway disorders.