Autism Spectrum Disorder Associated With a CACNA1I Variant of Uncertain Significance: A Case Report

TL;DR

A six-year-old girl with autism spectrum disorder was found to have a rare CACNA1I gene variant, which may be linked to her developmental delays and speech impairment.

Contribution

This case report adds to the growing evidence linking CACNA1I variants to neurodevelopmental disorders with speech impairment.

Findings

A heterozygous CACNA1I missense variant was identified in a child with ASD and significant developmental delays.

The variant is classified as a variant of uncertain significance and potentially de novo.

The child showed mild improvement with interventions but continued to have minimal language and adaptive functioning.

Abstract

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition with multifactorial etiologies, and accumulating evidence suggests that ion channel dysfunction may contribute to a subset of phenotypes. We report a six-year-old Saudi girl with early-onset and persistent deficits in social communication, profound speech impairment, stereotyped behaviors, sensory dysregulation, and significant adaptive and cognitive delays. Standardized assessments demonstrated moderate global delay (Vineland composite score 42), clinically significant social communication impairment (SRS-2 total T-score 64, with earlier documentation exceeding 90), and moderate nonverbal cognitive delay (Leiter-3 nonverbal IQ 43). Whole-exome sequencing (CentoGenome® MOX 1.0 Solo) identified a heterozygous CACNA1I missense variant (NM_021096.3:c.6028G>T; p.Ala2010Ser) classified as a variant of uncertain significance, not present in population databases and interpreted as potentially de novo, with a possible splice effect flagged despite largely benign in silico predictions. The child received multidisciplinary interventions, including ABA-based behavioral therapy, speech therapy, occupational therapy, and risperidone for behavioral dysregulation, with mild improvement in social responsiveness but persistent minimal language and limited adaptive functioning. This case adds to emerging reports linking CACNA1I variation to neurodevelopmental phenotypes characterized by prominent speech impairment and highlights the clinical challenge of counseling families when a potentially relevant de novo finding remains classified as a variant of uncertain significance.