Cognitive, Behavioral, and Eye Gaze Patterns in Patients with Germline Heterozygous PTEN Mutations and Autism Spectrum Disorder

Background: A growing body of literature has identified a relationship between the tumor suppressor gene PTEN and autism spectrum disorder (ASD) with macrocephaly (PTEN-ASD). Our initial cohort study found that PTEN-ASD patients had lower PTEN protein levels, abnormal brain white matter, and reduced cognitive function (IQ, working memory, and processing speed) relative to other macro- and normo-cephalic ASD patients and healthy controls. Yet, beyond this initial study, there is limited data on specific neurobehavioral phenotypes associated with PTEN-ASD.

Objectives: Our primary aim was to leverage detailed cognitive and symptom data collected in our initial cohort to compare the neurobehavioral characteristics of PTEN-ASD cases relative to other ASD and control cases. The secondary aim was to conduct a preliminary analysis of eye gaze data to social stimuli collected from a new cohort of PTEN cases.

Methods:  In our initial cohort (17 PTEN-ASD, 16 macro-ASD, 38 normo-ASD, and 14 controls), measures of autism symptoms, other psychopathology domains, child and family quality of life, attention, motor, and affective processing were collected. In our new cohort, remote eye gaze tracking was conducted from 8 PTEN patients and 18 age- and sex-matched healthy controls while they viewed brief videos depicting side-by-side faces, natural interactions, joint attention bids, and social versus abstract stimuli. Fixation duration was computed to specific regions-of-interest within each stimulus. In both samples, generalized estimating equation analyses examined group differences across neurobehavioral and eye gaze measures.

Results: Consistent with our previous findings, parent-reported and clinician-observed autism symptoms were highly similar across PTEN-ASD patients and other ASD groups. However, gross motor, and to a lesser extent, fine motor problems were more substantial in PTEN-ASD patients than other ASD groups (Figure 1a). PTEN-ASD patients were also rated as showing less emotion dysregulation (Figure 1b), anxiety/fear, aggression, and self-injury than other ASD groups. On cognitive testing, PTEN-ASD patients had problems with sustaining attention (Figure 1c), but were not impulsive. Affect and prosody recognition was impaired in PTEN-ASD relative to other ASD groups, but this was no longer significant after adjusting for IQ. The IQ reductions observed in PTEN-ASD patients were completely accounted for by impaired sustained attention, processing speed, and working memory. Quality of life, communication skills, and other psychopathology measurements were comparable across all ASD groups. In our new cohort, PTEN-ASD patients showed significant and dramatic reductions in eye gaze to socially-relevant regions-of-interest across 3 of the 4 stimuli (Figure 1d).

Conclusions: A PTEN-specific phenotype of ASD is emerging. The profile is characterized by generally reduced, but still variable, IQ - resulting from impairments in sustained attention, processing speed, and working memory. Also present is decreased fine and gross motor function, but PTEN-ASD patients ascertained to date had fewer behaviors suggestive of emotional dysregulation. Intriguingly, PTEN-ASD patients show highly similar autism symptom and eye gaze patterns to other ASD cases. These data support early referral of PTEN-ASD cases to occupational and physical therapy and suggest specific behavioral approaches to maximize sustained attention and reduce the impact of impaired processing speed and working memory.