CACNA1C – Intellectual Disability

CACNA1C (HGNC:1390) has emerged as a contributor to intellectual disability (Intellectual Disability) through multiple genetic studies. Variants in CACNA1C were identified in 14 Iranian patients from 7 unrelated families with ID and/or developmental delay (PMID:37543906) and were included among 159 cases of calcium channelopathies associated with ID/GDD in a systematic review (PMID:33985586).

Inheritance is primarily autosomal dominant, with heterozygous missense variants affecting the pore-forming α1 subunit. One representative variant is c.1081A>G (p.Thr361Ala). Segregation analyses document 7 additional affected relatives across families, supporting variant pathogenicity. The variant spectrum comprises predominantly missense changes, consistent with a gain-of-function mechanism.

Functional studies, including electrophysiological analyses in heterologous cells and modeling of channel kinetics, reveal altered voltage-dependent inactivation and window currents for several CACNA1C mutations, concordant with neuronal excitability defects. However, dedicated in vivo or rescue experiments in neurodevelopmental models remain scarce.

No significant conflicting evidence has been reported that disputes the role of CACNA1C in ID, although phenotypic heterogeneity and overlapping channelopathies underscore the need for genotype-phenotype correlation.

Collectively, the genetic and preliminary functional data support a Moderate clinical validity classification. CACNA1C testing should be considered in patients with unexplained intellectual disability, particularly when accompanied by developmental delay or seizures.

Key Take-home: Heterozygous CACNA1C missense variants confer a risk for intellectual disability via dysregulated calcium influx, informing diagnosis and genetic counseling.

References

• Archives of Iranian medicine • 2022 • Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability. PMID:37543906
• Orphanet journal of rare diseases • 2021 • Calcium channelopathies and intellectual disability: a systematic review. PMID:33985586

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