# Natural history of individuals with autism spectrum disorder and germline PTEN mutations

> **NIH NIH U54** · BOSTON CHILDREN'S HOSPITAL · 2021 · $389,287

## Abstract

Autism spectrum disorders (ASD) are an etiologically heterogeneous set of neurodevelopmental disorders
marked by social communication/interaction deficits and restricted/repetitive behaviors. Genetic studies have
identified a strong heritable component, yet >80% of ASD remains idiopathic. Marked heterogeneity has slowed
attempts to identify pathophysiology and related therapeutic targets. One promising strategy to reduce
complexity is to focus on subgroups with a specific genetic etiology, such as ASD associated with germline
heterozygous PTEN mutations (PTEN-ASD, who are always macrocephalic). In the last 4 years, we
characterized cross-sectional neurobehavioral and neurocognitive differences among PTEN-ASD, those with
PTEN mutations but no ASD (PTEN-no ASD) and macrocephalic ASD without PTEN mutations (Macro-ASD)
and begun longitudinal data collection in individuals aged 3-21. We propose a natural history study of the
neurophenotypic and molecular characteristics of PTEN-ASD with the goals of understanding risk management
and treatment planning as well as identifying sensitive biomarkers for intervention studies. We will recruit 170
(70 from current cohort) individuals with PTEN-ASD, Macro-ASD, and PTEN no-ASD, and expanding recruitment
to aged 18 months to 45 years. Data collected will include: (a) cancer occurrence, (b) autism and other behavioral
symptoms, (c) neurocognitive profiles, (d) adaptive function, (e) genomic modifiers, (f) protein levels from
PI3K/AKT/mTOR/S6K pathway, and (g) EEG, in order to: (Aim 1) Determine cross-sectional and longitudinal
neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range. This
aim seeks to describe initial levels and longitudinal changes in cancer occurrence, behavioral signs/symptoms,
and cognitive function in PTEN-ASD; (Aim 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and
those shared with other groups. This aim seeks to identify biomarkers that may be treatment targets in
intervention studies; and (Aim 3) Develop a comprehensive, multi-level, longitudinal model of PTEN-ASD to
inform future clinical trials and the development of consensus care guidelines. We will use data from Aims 1 and
2 and from TSC Associated Neuropsychiatric Disorders (TAND) Checklist (after validation). This first
comprehensive longitudinal evaluation of the phenotypic and molecular characteristics of PTEN ASD, to identify
specific molecular pathway and correlated neural abnormalities responsible for ASD symptoms in these
individuals, which can be ably compared to TSC and PMS. It is a crucial next step toward the development of
personalized genetic treatment approaches for PTEN-ASD. Prior to initiating further clinical trials, it will be critical
to identify treatment targets at the molecular, neurophysiological, and behavioral levels.

## Key facts

- **NIH application ID:** 10242080
- **Project number:** 5U54NS092090-08
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Charis Eng
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,287
- **Award type:** 5
- **Project period:** 2014-09-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242080

## Citation

> US National Institutes of Health, RePORTER application 10242080, Natural history of individuals with autism spectrum disorder and germline PTEN mutations (5U54NS092090-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242080. Licensed CC0.

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