Unpacking The Autism Spectrum Disorder Profile of Children With De Novo Disruptive GRIN2B Variants: A Quantitative and Qualitative Analysis

Abstract Background : Disruptive mutations to GRIN2B are considered a high-confidence genetic factor of autism spectrum disorder (ASD), yet only ~25% of patients with GRIN2B mutations are given a formal ASD diagnosis. Here, we generate a comprehensive understanding of the ASD profile in children with de novo disruptive GRIN2B variants, including social communication deficits and restricted and repetitive behaviors (RRBs). Methods : The ASD profile was measured in 34 children with disruptive GRIN2B variants, including clinically assessed ASD severity (subset of 16 children) and parental reports of ASD symptomology. GRIN2B ASD profiles were compared to 96 children with a different pathogenic ASD-associated mutation, as well as 55 children with ASD stratified based upon low (n = 14) or average (n = 41) nonverbal cognition. Following statistical group comparisons, unique GRIN2B ASD features were further characterized using qualitative analysis of clinical observations and case reports. Results : Both GRIN2B and pathogenic groups exhibited similar proportions of formal ASD diagnoses and clinically assessed ASD severity was similar across comparison groups. Parents endorsed fewer problematic social behaviors and impairing RRBs in certain categories, highlighting relative strengths in socioemotional reciprocity and fewer reported problems with rigidity or restricted interests. Contextualization of behaviors based upon clinical observations indicated a unique GRIN2B profile describing high motivation to approach others, but often inappropriate social responses. Atypical nonverbal communication and sensory seeking were evident. Limitations : This study is limited by the small sample size for the clinically assessed GRIN2B subset. Second, the ASD comparison group was older than the GRIN2B or Pathogenic groups. Lastly, we focus on ASD symptomology and do not fully characterize other psychiatric, behavioral, or medical comorbidities or link the ASD profile to the specific function of GRIN2B variants (e.g., loss or gain of function), which may be a critical next step for developing targeted interventions. Conclusions : We identify a unique ASD profile for children with disruptive GRIN2B variants involving strengths in social motivation/approach and reduced impairing RRBs. Continued work phenotyping GRIN2B should incorporate nuanced examination of these strengths in the context of the challenges faced by individuals with disruptive GRIN2B variants.