POLE2

Inheritance Pattern: AR

Disease ID:MONDO:0800128

Submitter: ClinGen

*POLE2* was first reported in relation to combined immunodeficiency due to *POLE2* deficiency in 2016 (Frugoni et al., PMID: 26365386). *POLE2* deficiency is characterized by combined immunodeficiency, recurrent respiratory infections, agammaglobulinemia, absent NK cells, T cell lymphopenia and neutropenia, absent circulating B cells, increased effector memory T cells, undetectable TRECs, severe dyspnea with hypoxia, hepatomegaly, and hypothyroidism. The mechanism of pathogenicity appears to be homozygous loss of function. The curation of *POLE2* related to *POLE2* deficiency includes both case-level and experimental evidence. One variant, a canonical splice site variant has been reported in a single individual (PMID: 26365386). Heterozygous carriers from this single family were reportedly not identified to have any clinical features associated with *POLE2* deficiency. This gene-disease relationship is also supported by experimental evidence. Cell cycle proliferation studies on the patient’s peripheral blood leukocytes and fibroblasts showed abnormal cell cycle activity. This was partially rescued when cultured fibroblasts from the patient was transfected with wild type *POLE2*-containing vector (PMID: 26365386). It is unclear if abnormal cell cycle activity as a result of loss of *POLE2* is a mechanism for immunodeficiency. 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 SCID/CID Gene Curation Expert Panel on the meeting date 05/16/2024 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0015131

Submitter: PanelApp Australia