Journal Article

Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns

Silver, Hailey, Zweifach, Jessica, Levy, Tess, Thurm, Audrey, Siper, Paige M., Greenberg, Rori, Sahin, Mustafa, Kolevzon, Alexander, Grice, Dorothy E., Soorya, Latha Valluripalli, Berry-Kravis, Elizabeth, Bernstein, Jonathan A., Buxbaum, Joseph D., Soufer, Renee

2025

Overview

Background SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on laboratory-based in vivo and in vitro studies with few prospective clinical studies in humans. Methods A remote assessment battery was comprised of caregiver interviews with a psychiatrist, psychologists, and a genetic counselor, caregiver-reports, and review of records. Results from this cohort were reported using descriptive statistics. An age-matched sample of participants with SHANK3 haploinsufficiency (Phelan-McDermid syndrome, PMS) was used to compare adaptive behavior between the two groups. Results All ten participants demonstrated delays in adaptive behavior, with most motor skills preserved and a weakness in communication. According to parent report, 90% of participants carried a formal diagnosis of ASD, 50% of participants carried a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and mild-to-moderate developmental delays were noted. Sensory hyperreactivity and seeking behaviors were more pronounced than sensory hyporeactivity. Medical features included hypotonia, recurrent ear infections, and gastrointestinal abnormalities. No similar facial dysmorphic features were observed. Compared to PMS participants, individuals with SHANK2 disorder had significantly higher adaptive functioning. Conclusions Consistent with previous studies of SHANK2 disorder, these results indicate mild to moderate developmental impairment. Overall, SHANK2 disorder is associated with developmental and adaptive functioning delays, high rates of autism, including sensory symptoms and repetitive behaviors, and ADHD. This study was limited by its remote nature, diverse age range, and the homogeneous racial and ethnic sample. Future studies should examine larger, diverse cohorts, add cognitive testing, capture longitudinal data, and include in-person assessments.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Adult / Attention Deficit Disorder with Hyperactivity - genetics / Attention deficit hyperactivity disorder / Autism / Autism spectrum disorder / Autism Spectrum Disorder - genetics / Autism Spectrum Disorder - physiopathology / Behavior / Biomedical and Life Sciences / Biomedicine / Caregivers / Child / Child development deviations / Child, Preschool / Chromosome Deletion / Chromosome Disorders - genetics / Chromosome Disorders - physiopathology / Chromosomes, Human, Pair 22 - genetics / Cohort analysis / Cohort Studies / Development and progression / Developmental delay / Developmental disabilities / Developmental Disabilities - genetics / Developmental Disabilities - physiopathology / Diagnosis / Disability / Female / Gene deletion / Haploinsufficiency / Human Genetics / Humans / Hyperreactivity / Intellectual and developmental disability / Intellectual disabilities / Intellectual Disability - genetics / Male / Motor skill / Nerve Tissue Proteins - genetics / Neurodevelopmental disorders / Neurology / Neuropsychology / Neurosciences / Pediatrics / Phenotype / Proteins / Psychiatry / Quality of life / Questionnaires / Risk factors / SHANK2 / Skills / Standard scores