Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: ELF4

Green List (high evidence)

Comment on mode of inheritance: As there are three unrelated female patients reported with heterozygous ELF4 variants and autoinflammatory disorder, the MOI should be updated to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' in the next GMS update.

The 'Skewed X-inactivation' tag has also been added as skewed X chromosome inactivation patterns were observed in all three female patients in the same publication.

Created: 13 Jun 2025, 3:44 p.m. | Last Modified: 13 Jun 2025, 3:49 p.m.

Panel Version: 8.14

PMID:39976696 reported three unrelated paediatric female patients, who are all heterozygous for ELF4 variants. Similar to reported male patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhoea with colonoscopy showing ulcers in the colon. Skewed X chromosome inactivation patterns were observed in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.

Created: 13 Jun 2025, 3:41 p.m. | Last Modified: 13 Jun 2025, 3:41 p.m.

Panel Version: 8.11

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Autoinflammatory syndrome, familial, X-linked, Behcet-like 2, OMIM:301074

Publications

• 34326534
• 35266071
• 36823308
• 38231408
• 38773005
• 39563044
• 39976696

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:59 a.m. | Last Modified: 8 Mar 2022, 10:59 a.m.

Panel Version: 2.532

Comment on list classification: Upgraded from Red to Amber but there is enough evidence to rate this gene as Green at the next GMS panel update. At least two variants identified in three unrelated individuals with autoinflammatory disease characterised by fever, oral ulcers and mucosal inflammation. Supported by functional studies and mouse model.

Created: 14 Sep 2021, 10:46 a.m. | Last Modified: 14 Sep 2021, 10:46 a.m.

Panel Version: 2.461

Green List (high evidence)

Multiple male patients with similar phenotype and functional data

Created: 12 Sep 2021, 11:13 a.m. | Last Modified: 12 Sep 2021, 11:13 a.m.

Panel Version: 2.458

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Ulcers; fever; inflammatory bowel disease; autoinflammatory condition

Publications

• PMID: 34326534

Green List (high evidence)

Tyler et al. ( https://www.nature.com/articles/s41590-021-00984-4 ) identified 3 males from unrelated families carrying hemizygous loss-of-function mutations presenting with early-onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade.

Created: 30 Jul 2021, 8:14 p.m. | Last Modified: 30 Jul 2021, 8:14 p.m.

Panel Version: 2.452

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Inflammatory bowel disease; IBD; mucosal inflammation; fever; ulcers; Behcet-like disease

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Comment when marking as ready: Three negative expert reviews. No phenotype in OMIM. No disease associated in Gen2Phen.

Created: 11 May 2016, 10:41 a.m.

Comment on mode of pathogenicity: unknown

Created: 10 May 2016, 11:01 a.m.