Submission Details

FOXI3 was first reported in relation to autosomal dominant T-cell immunodeficiency in 2022 (Ghosh et al., PMID: 35987349). T-cell immunodeficiency is a broad classification of disorders that affect the cell-mediated aspects of the immune response, wherein circulating numbers of T lymphocytes are decreased or ineffective. At least 2 variants (nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in FOXI3 have been reported in individuals with the following disease entities: T-cell immunodeficiency and Craniofacial microsomia 2. Per criteria outlined by the Clingen Lumping and Splitting Working Group, we found a difference in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, T-cell immunodeficiency (MONDO:0003780) and Craniofacial microsomia 2 (MONDO:0958194). The split curation for Craniofacial microsomia 2 will be assessed separately. Variants in this gene have been reported in at least 2 probands in 1 publication (PMID: 35987349). The mechanism for disease is haploinsufficiency (PMID: 35987349). This gene-disease relationship is supported by knockout and variant mouse models presenting with absence or decreased weight of thymus (. PMID: 31600545, PMID: 37041148). In summary, there is limited evidence to support the relationship between FOXI3 and T-cell immunodeficiency. 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 GCEP on the meeting date August 21st 2025 (SOP Version 11).