Submission Details

CA8 was first reported in relation to autosomal recessive cerebellar ataxia in 2009 (Turkmen et al., PMID: 19461874). CA8-related cerebellar ataxia is characterized by features of cerebellar ataxia such as wide-based or quadrupedal gait, intention tremor, dysarthria, cerebellar atrophy, and developmental delay with or without cognitive delay (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436). Six variants (5 missense and 1 truncating) that have been reported in 12 individuals (6 probands) in 6 publications (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436) are included in this curation. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence. The ataxic mouse model 'Rigoletto' (rig) carries a 19-bp deletion in Car8, the mouse homolog of CA8. Studies of cerebellar Purkinje cells in these mice showed decreased spontaneous excitatory transmission with a reportedly lower number of functional synapses. Mutants also showed abnormalities of the extension of climbing fibers to distal Purkinje cell dendrites, of parallel fibers and dendritic spines (including free spines that did not form normal synapses), and multiple synaptic varicosities. The authors concluded that Car8 plays a critical role in synaptogenesis and/or maintenance of proper synaptic morphology and function in the cerebellum (PMID: 17376701). Expression studies also indicated specific expression of CAR8 in cerebellar Purkinje cells and minimal to absent expression in the spinal cord and cerebral cortex (PMIDs: 16118194, 31693170).

In summary, there is moderate evidence supporting the relationship between CA8 and autosomal recessive cerebellar ataxia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Autism and Intellectual Disability Gene Curation Expert Panel on January 16, 2024 (SOP Version 10).

CA8 was first reported in relation to autosomal recessive cerebellar ataxia in 2009 (Turkmen et al., PMID: 19461874). CA8-related cerebellar ataxia is characterized by features of cerebellar ataxia such as wide-based or quadrupedal gait, intention tremor, dysarthria, cerebellar atrophy, and developmental delay with or without cognitive delay (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436). Six variants (5 missense and 1 truncating) that have been reported in 12 individuals (6 probands) in 6 publications (PMIDs: 19461874, 21812104, 21937992, 27217339, 31693170, 32808436) are included in this curation. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence. The ataxic mouse model 'Rigoletto' (rig) carries a 19-bp deletion in Car8, the mouse homolog of CA8. Studies of cerebellar Purkinje cells in these mice showed decreased spontaneous excitatory transmission with a reportedly lower number of functional synapses. Mutants also showed abnormalities of the extension of climbing fibers to distal Purkinje cell dendrites, of parallel fibers and dendritic spines (including free spines that did not form normal synapses), and multiple synaptic varicosities. The authors concluded that Car8 plays a critical role in synaptogenesis and/or maintenance of proper synaptic morphology and function in the cerebellum (PMID: 17376701). Expression studies also indicated specific expression of CAR8 in cerebellar Purkinje cells and minimal to absent expression in the spinal cord and cerebral cortex (PMIDs: 16118194, 31693170).

In summary, there is moderate evidence supporting the relationship between CA8 and autosomal recessive cerebellar ataxia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 16, 2024 (SOP Version 10).