NFAT5

Inheritance Pattern: AD

Disease ID:MONDO:0003778

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0021094

Submitter: ClinGen

*NFAT5* was first reported in relation to autosomal dominant immunodeficiency disease in 2022 (PMID: 36238298). This condition is characterized by impaired adaptive and innate immune responses, including lymphopenia, abnormal B‑ and T‑cell function, poor antigen‑specific responses, and susceptibility to infections, particularly from Epstein-Barr virus. Two missense variants that have been reported in 2 probands in 1 publication (PMID: 36238298) are included in this curation. The mechanism of pathogenicity is presumed to involve haploinsufficiency of *NFAT5,* consistent with impaired osmoprotective gene induction and reduced lymphocyte survival under stress conditions (PMID: 10051678). This gene–disease relationship is also supported by experimental evidence, including biochemical function studies showing that *NFAT5* is required for tonicity‑responsive gene expression in lymphocytes (PMID: 10051678) and multiple mouse models demonstrating reduced thymic cellularity, peripheral lymphopenia, impaired lymphocyte proliferation, and diminished antigen‑specific immune responses in NFAT5‑deficient mice (PMIDs: 12421923, 15247420). These model systems together support a biological role for *NFAT5* in immune homeostasis, although they cannot model human‑specific phenotypes such as EBV susceptibility. 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 Primary Immune Regulatory Disorders Gene Curation Expert Panel on the meeting date March 19, 2024 (SOP Version 9).