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Neurobehavioral Signatures in Overgrowth Intellectual Disability Syndromes: Dissecting Genotype-Phenotype
Aaron D Besterman1,2, Gerhard Hellemann3, Irma Gutierrez-Mejia4
1University of California San Diego Department of Psychiatry, Division of Child and Adolescent Psychiatry, San Diego, California, USA.
Medrxiv : the Preprint Server for Health Sciences
|September 2, 2025
Summary
Smith-Kingsmore Syndrome (SKS) and PTEN Hamartoma Tumor Syndrome (PHTS) show distinct neurobehavioral profiles. SKS has severe motor and adaptive deficits, while PHTS presents unique features like neonatal teeth, aiding diagnosis.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Overgrowth intellectual disability syndromes (OGIDs) linked to the PI3K-AKT-MTOR pathway cause neurobehavioral issues.
- PTEN Hamartoma Tumor Syndrome (PHTS) is characterized, but Smith-Kingsmore Syndrome (SKS) neurobehavioral aspects remain unclear.
Purpose of the Study:
- To delineate the neurobehavioral profile of SKS and compare it with PHTS, autism macrocephaly, and controls.
- To identify shared and distinct features across these related genetic disorders.
- To explore genotype-phenotype correlations and develop diagnostic models.
Main Methods:
- Comprehensive neurobehavioral assessments in 17 SKS individuals and comparison with existing PHTS, autism macrocephaly, and control cohorts.
- Genotype-phenotype correlation analyses and recursive partitioning for diagnostic models.
- Evaluation of motor, adaptive, social, and executive functioning, alongside novel clinical features.
Main Results:
- SKS individuals exhibited significant impairments across multiple neurobehavioral domains compared to controls.
- SKS showed more severe motor and adaptive deficits than PHTS, with similar executive dysfunction.
- Novel features like immune dysregulation and neonatal teeth (in PHTS) were identified; diagnostic models showed above-chance accuracy.
Conclusions:
- Distinct neurobehavioral profiles exist between SKS and PHTS, indicating differential pathway impacts on neural development.
- Identified novel phenotypic features and diagnostic markers, expanding the clinical spectrum.
- Variant pathogenicity scores have limited predictive value, underscoring the need for comprehensive individual assessments.
Keywords:
Genotype-phenotype correlationIntellectual disabilityNeurobehavioral phenotypeNeurodevelopmental disordersOvergrowthMore Related Videos
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