Mendeliome
Gene: IRF4 Green List (high evidence)Green List (high evidence)
Classified as STRONG by Antibody Deficiency ClinGen GCEP on 28/08/2024 - https://search.clinicalgenome.org/CCID:008358
ClinGen downgraded classification from Definitive to strong due to lack of patients described thus far.
4 variants have been identified in 15 patients and biallelic LoF is the suggested mechanism of disease.Created: 16 Sep 2024, 3:22 a.m. | Last Modified: 16 Sep 2024, 3:22 a.m.
Panel Version: 1.2013
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
combined immunodeficiency MONDO:0015131
Publications
I don't know
Comment on list classification: Single case and mouse model for recessive combined immunodeficiencyCreated: 1 Mar 2021, 6:31 a.m. | Last Modified: 1 Mar 2021, 6:31 a.m.
Panel Version: 0.6502
A single case with a homozygous splice variant inherited by uniparental isodisomy, and previously reported supporting null animal models.Created: 1 Mar 2021, 6:30 a.m. | Last Modified: 1 Mar 2021, 6:30 a.m.
Panel Version: 0.6501
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Combined immunodeficiency
Publications
Green List (high evidence)
PMID 36662884: Seven individuals with profound CID from six kindreds of diverse ethnic origins (Fig. 1A). All affected individuals suffered with early onset (<1 year of age) recurrent sinopulmonary infections, with the opportunistic pathogen Pneumocystis jirovecii causing pneumonia in most individuals. p.T95R variant found in all patients. Extensive functional data including knockout mouse model. The heterozygous IRF4T95R variant found in multiple unrelated families caused a fully penetrant, severe very early-onset immunodeficiency characterized by greatly enhanced susceptibility to opportunistic pathogens such as P. jirovecii and weakly pathogenic mycobacteria.Created: 15 Oct 2023, 7:19 a.m. | Last Modified: 15 Oct 2023, 7:19 a.m.
Panel Version: 1.1293
Single family reported with Whipple's disease and a rare missense in IRF4. Younger members of the family had the same variant, leading the authors to speculate about age-dependent penetrance. GWAS indicates link with skin/hair/eye pigmentation.Created: 16 Apr 2020, 11:40 a.m. | Last Modified: 16 Apr 2020, 11:40 a.m.
Panel Version: 0.2290
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Immunodeficiency 131, MIM# 621097
Publications
Phenotypes for gene: IRF4 were changed from Combined immunodeficiency, MONDO:0015131, IRF4-related to Immunodeficiency 131, MIM# 621097
Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency to Combined immunodeficiency, MONDO:0015131, IRF4-related
Publications for gene: IRF4 were set to 29537367; 29408330
Gene: irf4 has been classified as Green List (High Evidence).
Gene: irf4 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724 to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency
Publications for gene: IRF4 were set to 29537367
Mode of inheritance for gene: IRF4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: irf4 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: IRF4 were changed from to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724
Publications for gene: IRF4 were set to
Mode of inheritance for gene: IRF4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: irf4 has been classified as Red List (Low Evidence).
gene: IRF4 was added gene: IRF4 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: IRF4 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.