POLD2 was first reported in relation to an autosomal recessive non-severe combined immunodeficiency due to polymerase delta deficiency in 2019 (Conde, et al., 2019, PMID:31449058). To date, there is only one proband with a POLD2 homozygous missense variant and the disease. The proband displayed severe intellectual disability, short stature, recurrent upper and lower respiratory infections, CD4+ T, B, and NK cell lymphopenia, and high frequency of CCR7-CD45RA+ TEMRA CD8+ T cells. Patient fibroblasts showed slower S phase progression with faster replication fork progression compared to healthy donor fibroblasts and reduced number of replication origin initiation events. This individual scored to a total of .5 points for genetic evidence.
This gene-disease association is also supported by one animal model (PMID:36528861). Homozygous POLD2 knock out mice were embryonic lethal by the gastrulation stage with an apparent deficiency in cellular proliferation, as mutant cells failed to grow from the zona pellucida. The gene-disease association is also supported by biochemical function showing that POLD2 provides the scaffolding for the assembly of DNA polymerase Delta, which is a critical enzyme for both DNA replication and DNA repair. Additionally, a co-IP assay has shown that POLD2 co-immunoprecipitates with POLD1, the catalytic subunit of DNA polymerase delta that has also been implicated in non-severe combined immunodeficiency due to polymerase delta deficiency. In summary, this curation reached a level of Limited due to the small number of published patients. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date February 16th (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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