Submission Details

ELF4 was first reported in relation to X-linked inheritance autoinflammatory syndrome, familial Behcet-like 2 in 2021 (Tyler et al., PMID: 34326534). X-linked familial Behcet-like autoinflammatory syndrome-2 is an X-linked recessive disorder characterized by inflammatory symptoms present in males within the first decade of life. Affected males most often present with oral mucosal ulceration and skin inflammation. Other variable features include gastrointestinal ulceration, arthritis, recurrent fevers, and iron deficiency anemia.

ELF-4 deficiency is also known as X-linked deficiency in ELF4 (DEX). It is characterized by mucosal inflammation and features resembling inflammatory bowel disease (IBD), in addition to the Behcet’s phenotype. ELF4 is a transcription factor that regulates immune responses in macrophages. The loss of ELF4 leads to hyperinflammatory response in macrophages, specifically with regard to IL-17 and TREM-1 signaling, which contributes to the phenotype. TREM-1 blockade has been shown to mitigate inflammation and intestinal pathology in ELF-4-deficient mouse models. More recently it has been shown that ELF4 also regulates the inflammatory potential of CD4+ T cells (Bender et al, The Journal of Immunology, May 2024, https://doi.org/10.4049/jimmunol.212.supp.1259.5567). The clinical phenotype of ELF-4 deficiency includes fevers, oral and GI ulcers, abdominal pain, diarrhea, and arthritis. DEX is primarily observed in males though skewed X-chromosome inactivation and disease has been reported in females (Zhao R et al, PMID: 39976696).

Seven variants (missense, nonsense, frameshift) that have been reported in nine probands in four publications (PMIDs: 34326534, 35266071, 38231408, 36823308) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies) (PMIDs: 35266071, 34326534). Mouse studies including both knock-in (W250S mice; equivalent to the human W251S) and knock-out (Elf4 KO) mice showed that there was reduced perforin expression in cytotoxic T lymphocytes. Both the Elf4 KO and W250S mice indicate that the patient-derived ELF4 variants are loss-of-function. Further, mice harboring the W230R missense variant (equivalent to the human W231R) showed significantly decreased viral clearance compared to those from WT mice. Bone marrow-derived macrophage (BMDM) from mutant mice showed similar impairment suggesting impaired ability for viral clearance.

In summary, there is definitive evidence supporting the relationship between ELF4 and X-linked inheritance autoinflammatory syndrome, familial Behcet-like 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time This classification was approved by the ClinGen PIRD GCEP on the meeting date Jne 9, 2025 (SOP Version 10.1).