A common underdiagnosed highly penetrant monogenic cause of Autism affecting sensory processing and language

Abstract

Background:
Mutations in the SHANK3 gene represent a highly penetrant and often underdiagnosed monogenic cause of autism, accounting for approximately 1–2% of ASD cases. SHANK3 plays a critical role in glutamatergic signaling, directly influencing sensory processing and early language development. Furthermore, recent studies link SHANK3 function to normal speech development and the broader phenotype of ASD symptoms.

This study investigates SHANK3 copy number variations (CNVs) in 70 Egyptian children diagnosed with autism, examining correlations with their language development and sensory profiles. Using standardized tools like the Autism Diagnostic Interview-Revised, Arabic Preschool Language Scale, and the Sensory Profile, along with molecular analysis via MLPA (Multiplex Ligation-dependent Probe Amplification), the research identified three cases with duplications in the 22q13.33 region. Two duplications included SHANK3, while one affected the flanking region.

Each case displayed different language impairments, ranging from non-verbal autism to stereotyped speech, alongside comorbidities such as ADHD, epilepsy, and hyperactivity. Sensory assessment revealed that all three showed atypical performance in the low-energy/weak domain, highlighting SHANK3’s role in sensory modulation.

Conclusion:
Both SHANK3 deletions and duplications may contribute to the complex genotype-phenotype landscape of autism. These findings support the need for genetic screening in special education for autism and reinforce the importance of early intervention strategies informed by ASD treatment research, including input from institutions such as the National Autistic Society.