A Prospective, Longitudinal Study of Caregiver-Reported Adaptive Skills and Function of Individuals with HNRNPH2-related Neurodevelopmental Disorder

Objectives: This study presents a cohort of individuals in a natural history study with de novo pathogenic missense variants in HNRNPH2 causative of HNRNPH2-related neurodevelopmental disorder (NDD) to describe individuals' adaptive functional abilities.

Methods: We measured adaptive function using the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) and the Vineland Adaptive Behavior Scale (VABS-III). Results were compared using inferential statistics and regression analysis.

Results: Sixty-seven individuals carried known pathogenic or likely pathogenic variants in HNRNPH2. Thirty-five participants (2.89-42.04 years, 83% female) and caregivers completed PEDI-CAT assessments with 25 of these participants completing the VABS-III. Sixteen, three and two participants completed a follow-up PEDI-CAT assessment at one, two and three years respectively. Individuals had mean normative scores less than age-matched peers across all domains on both PEDI-CAT and VABS-III measures, with 91% participants < 5^th percentile on both the PEDI- CAT and VABS-III. Verbal and ambulatory participants had significantly higher PEDI-CAT scores across all domains, using both raw and normative data. There was no significant change in PEDI-CAT scores over 3 years.

Conclusions: Overall scores, both raw and normative, are low across all individuals with HNRNPH2-related NDD using both the PEDI-CAT and VABS-III. PEDI-CAT normative scores do not likely represent the clinical variability, but raw scores may be able to capture functional variability. In a small sample, longitudinal data from the PEDI-CAT domain scores demonstrate stability in performance at 3 years.Trial Registration: ClinicalTrials.gov NCT03492060.