Relevance to Autism

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013). Lipman et al., 2022 reported 47 individuals with 33 unique pathogenic or likely pathogenic variants in CACNA1A; developmental delay/intellectual disability was observed in 96% of affected individuals, and autism spectrum disorder was reported in 23% of affected individuals.

Molecular Function

This gene encodes the pore-forming alpha-1A subunit, which is predominantly expressed in neuronal tissue, for voltage-dependent calcium channels. Mutations in this gene are associated with several neurological disorders: episodic ataxia, type 2 (OMIM 108500); migraine, familial hemiplegic, 1 (OMIM 141500); and spinocerebellar atxia 6 (OMIM 183086).

External Links

References