Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: IFIH1

Green List (high evidence)

Comment on mode of inheritance: There are numerous patients reported with both mono- and bi-allelic variants in IFIH1. Heterozygous gain-of-function variants are thought to result in Aicardi-Goutieres syndrome (autoimmune disorder), while putative LoF variants have been reported in patients with inborn errors of immunity and early-onset IBD. Many cases harbour relatively common hypomorphic variants, which slightly impair MDA5 activity and increase susceptibility to infections with incomplete penetrance. True recessive cases are relatively rare, with only 6 individuals reported with biallelic rare variants in IFIH1 (PMIDs: 29018476; 34185153). Based on available evidence, MOI should remain BOTH monoallelic and biallelic, autosomal or pseudoautosomal on this panel.

Created: 9 Sep 2026, 3:53 p.m. | Last Modified: 9 Sep 2026, 3:55 p.m.

Panel Version: 9.105

PMID: 38757311 Najm et al., 2024
Report of nine patients suffering from recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C) identified with putative loss-of-function IFIH1 variants by WES.
All patients revealed signs of lymphopaenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19 or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C.
Variant c.2807+1G>A, homozygous in the most severe case, has MAF = 0.01909 in gnomAD, with 86 homozygotes noted.

PMID: 34185153 Cananzi et al., 2021
Cohort of 42 Very Early Onset IBD probands from Italy and USA. WES identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD: homozygous p.Asp673Ilefs*5 in Patient 1, and het LoF variants in others (2 frameshift, 2 splice, and 3 stop-gain variants). Among these, two patients also carried a second hypomorphic missense variant each, with some partial function; two individuals had rare missense variants in trans with protein function described to be normal; two patients only harboured 1 LoF IFH1 variant; P7 had 2 IFH1 variants in cis: c.2807+1G>A and p.Thr702Ile. In summary, 3 monoallelic individuals and 5 biallelic individuals were reported.
Parents of the homozygous individual were unaffected. In 2/3 monoallelic cases, the LoF variants were inherited from an unaffected parent as well - incomplete penetrance. Only P1 with a homozygous IFIH1 variant suffered from recurrent infections, with early neonatal sepsis.

Functional effect of each variant was tested using a dual luciferase reporter assay was used to test for activity of the allele driven by the IFNB1 promoter.

PMID: 34726731 Chen et al., 2021
Report of two unrelated children with enterovirus rhombencephalitis with IFIH1 variants. Seq method: trio WES.
P1 - male, born to nonconsanguineous parents of sub-Saharan African origin. He was comp het for IFIH1 variants c.965delT, p.F322fsTer2 and hypomorphic c.838G>A, p.D280N.
P2 - male, born to nonconsanguineous parents of Spanish origin. He was homozygous for IFIH1: c.1641+1G>C - AF in European population in gnomAD is 0.01353, with total 122 homozygotes reported.
The patients have not suffered any other severe infectious disease since hospitalization for EV encephalitis.

PMID: 29018476 Zaki et al. 2017
Egyptian female patient with microcephaly, severe psychomotor retardation, seizures and cataracts (attributed to a homozygous PHGDH, c.1273G>A (p.Val425Met) variant causing 3-phosphoglycerate dehydrogenase deficiency). She also suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization - attributed to a homozygous IFIH1 c.2665A>T (p.Lys889*) variant - rare in gnomAD v4.

PMID: 28716935 Asgari et al., 2017
Cohort of 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus.
Eight study participants carried putative LoF variants in IFIH1. Four study participants carried a splicing variant, rs35732034 / IFIH1 c.2807+1G>A, one in homozygous and three in heterozygous form. It was shown to cause exon 14 skipping. This variant is present in gnomAD v4.1.1. with MAF = 0.01909; total of 86 homozygotes reported.
1 individual was het for rs35744605 (IFIH1 p.Glu627Ter) - MAF = 0.006540 in gnomAD, 30 hom.
Three individuals with RSV bronchiolitis were het for rs35337543 (denoted as p.Leu509_Glu547del change in the paper, but c.1641+1G>C in ClinVar).

PMID: 28606988 Lamborn et al., 2017
5yo female patient with inherited MDA5 deficiency (manifesting in recurrent viral respiratory infections requiring frequent hospitalizations) and a homozygous IFIH1 variant c.1093A>G, p.Lys365Glu. At 40 days, she had she had respiratory failure from concurrent HRV/enterovirus and influenza B virus infections.
The p.Lys365Glu variant is fairly common (MAF 0.004291 in gnomAD v4.1.1, 2 homozygotes reported). Seq method: WES.
Functional: Nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV.

IFIH1 is associated with AD Aicardi-Goutieres syndrome 7, OMIM:615846, AD Singleton-Merten syndrome 1, OMIM:182250, and AR Immunodeficiency 95, OMIM:619773 (Accessed 9th Sept 2026).

Created: 9 Sep 2026, 2:46 p.m. | Last Modified: 9 Sep 2026, 3:43 p.m.

Panel Version: 9.105

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Immunodeficiency 95, OMIM:619773; immunodeficiency 95, MONDO:0030692; Aicardi-Goutieres syndrome 7, OMIM:615846; Aicardi-Goutieres syndrome 7, MONDO:0014367

Publications

• 28606988
• 28716935
• 29018476
• 34185153
• 34726731
• 38757311

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Note that an allelic autosomal recessive LOF disorder has been described as causing susceptibility to RNA viruses (PMID 28606988)

Created: 29 Jun 2018, 2:18 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Comment on list classification: Changed Amber to Green from external review comment and further publications to support gene-disease association

Created: 4 Jul 2018, 11:01 a.m.

Comment on mode of pathogenicity: Allelic autosomal dominant GOF disorder has been described as causing Aicardi-Goutieres syndrome 7. Allelic autosomal recessive LOF disorder has been described as causing susceptibility to RNA viruses

Created: 4 Jul 2018, 10:59 a.m.

Comment on mode of inheritance: changed form AD to both monoallelic and biallelic

Created: 4 Jul 2018, 10:55 a.m.

Comment on phenotypes: added specific MOI to the two observed immunological phenotypes associated to this gene

Created: 4 Jul 2018, 10:52 a.m.

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): IFIH1 .PanelApp HGNC gene symbol check: IFIH1 . IUIS Disease: MDA5 deficiency . IUIS Inheritance: AR .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: Somatic and hematopoietic. IUIS Associated features: Rhinovirus and other RNA viruses. IUIS Major category: Defects in Intrinsic and Innate Immunity. IUIS Subcategory: Predisposition to Severe Viral Infection. // OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): IFIH1 (GOF) .PanelApp HGNC gene symbol check: IFIH1 . IUIS Disease: Aicardi-Goutieres syndrome 7 (AGS7) . IUIS Inheritance: AD .T cells: Nl number, nl/low function, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Classical AGS, SLE, SP, SMS. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Type 1 Interferonopathies.

Created: 2 Jul 2018, 10:53 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: IFIH1, GRID_Gene_Symbol: IFIH1, GRID_Transcript_ENS_Community submitted: ENST00000263642, GRID_Transcript_RefSeq: NM_022168.3, GRID_Transcript_ENS_used_on_Production: ENST00000263642

Created: 17 Apr 2018, 12:12 p.m.