Submission Details

CACNG2 was first reported in relation to autosomal dominant intellectual disability (the disease term linked with this gene in resources such as OMIM and Monarch) in 2011 (Hamdan et al., PMID: 21376300). Later, rare de novo variants in CACNG2 were also reported in probands with epilepsy and autism spectrum disorder (ASD). Due to the variable presentation in the reported probands, we decided to curate for the generic term complex neurodevelopmental disorder. Evidence supporting this gene-disease relationship is minimal.

Only three patients with non-overlapping phenotypes have been reported to carry rare variants in CACNG2, with insufficient evidence for disease causality. A de novo missense variant was reported in a patient with moderate intellectual disability and no epilepsy; functional studies of the variant showed reduced binding to AMPA receptors and decreased glutamatergic transmission (Hamdan et al., PMID: 21376300). A de novo microdeletion encompassing exon 2 of CACNG2 and resulting in an in-frame deletion was reported in an individual with ASD (Brandler et al., PMID: 27018473). In addition, a de novo splice site variant was reported in a patient with focal Rolandic seizures and borderline IQ (Rudolf et al., PMID: 32600977). CACNG2 encodes an AMPA receptor regulatory protein involved in synaptic plasticity. Two mouse models with spontaneous recessive mutations disrupting Cacng2 exhibit ataxic gait and absence seizures, together with defects in the cerebellum and inner ear (PMIDs: 12925883, 15283975). The relevance of these phenotypes to those observed in individuals with heterozygous CACNG2 variants is unclear, so this experimental evidence was not scored. In summary, there is limited evidence to support the gene-disease relationship between CACNG2 and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 2021/07/07 (SOP Version 8).