Submission Details

Proliferating cell nuclear antigen (PCNA) was first reported in relation to autosomal recessive ataxia-telangiectasia like disorder in 2014 (Baple et al., PMID: 24911150). Among the reported cases: ataxia, photosensitivity, telangiectasias, and some degree of intellectual disability have been observed in biallelic variant carriers. The phenotypic spectrum may be more diverse but more cases are needed to confirm. Only two missense variants have been associated with PCNA-related disease in five families across 3 publications (PMIDs: 24911150, 33426167, 36990216). Segregation of biallelic PCNA variants with disease is consistent across the 5 families, with every homozygous carrier being affected with similar features. The mechanism of pathogenicity is unclear but not expected to be a result of haploinsufficiency as PCNA knockout mice are embryonic lethal (PMID: 18854411). It is known though, that PCNA is a key protein in DNA synthesis and repair and variation in genes with similar function have been associated with disease characterized by similar features (PMID: 39622612). This gene-disease relationship is also supported by biochemical, protein interaction, and functional data in patient cells PMIDs: 8621631, 28073635, 36990216). There is evidence of altered protein stability for both variants, altered protein interaction with genes associated with similar disease features but not entirely overlapping, and that PCNA is involved in DNA repair. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebella Ataxia GCEP on the meeting date, April 9th, 2025 (SOP Version 11).