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

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.