CACNA1G – Intellectual Disability

The clinical evidence for CACNA1G in intellectual disability is derived from both copy number variant analyses and targeted sequencing efforts demonstrating an association with neurodevelopmental impairment.

In a familial case, a deletion encompassing CACNA1G segregated with intellectual disability in two affected relatives (PMID:23949819). A systematic review of calcium channelopathies identified CACNA1G variants in individuals with intellectual disability and global developmental delay across multiple reports (PMID:33985586). More recently, de novo missense variants in CACNA1G have been detected in neurodevelopmental disorder cohorts, including Rett and West syndromes and Lennox–Gastaut syndrome patients with severe developmental delay (PMID:32736238).

The inheritance pattern is predominantly autosomal dominant with de novo occurrence, and limited segregation beyond one multiplex family has been demonstrated (1 additional affected relative). The variant spectrum in CACNA1G associated with intellectual disability includes heterozygous microdeletions removing the gene and single‐nucleotide missense changes.

A representative missense variant, c.2727G>T (p.Leu909Phe), identified in infantile‐onset developmental and epileptic encephalopathy cohorts, illustrates gain‐of‐function effects with hyperpolarizing shifts in activation and slowed deactivation kinetics (PMID:32878331).

Functional electrophysiological studies in heterologous expression systems reveal that pathogenic CACNA1G variants display altered gating properties consistent with enhanced channel activity, aligning with a proposed gain‐of‐function mechanism contributing to neurodevelopmental phenotypes.

Although evidence supports a role for CACNA1G in intellectual disability, the genetic data are limited by small cohort sizes, minimal segregation, and the contribution of multi‐gene channelopathy studies; further large‐scale familial and case–control analyses are needed. Key Take-home: Autosomal‐dominant CACNA1G variants lead to intellectual disability through gain‐of‐function T-type calcium channel alterations, informing diagnostic sequencing and potential genotype-directed functional assays.

References

• American journal of medical genetics. Part A • 2013 • Osteogenesis imperfecta, tricho-dento-osseous syndrome and intellectual disability: a familial case with 17q21.33-q22 (COL1A1 and DLX3) deletion and 7q32.3-q33 duplication resulting from a reciprocal interchromosomal insertion. PMID:23949819
• Orphanet journal of rare diseases • 2021 • Calcium channelopathies and intellectual disability: a systematic review. PMID:33985586
• Journal of the neurological sciences • 2020 • De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies. PMID:32736238
• International journal of molecular sciences • 2020 • Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy. PMID:32878331

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