Intellectual disabilityGene: IRF2BPL Green List (high evidence)
Comment on phenotypes: added MIMid from OMIM and phenotype data
Created: 31 Oct 2018, 3:31 p.m.
Comment on list classification: New gene suggested by external reviewer and reviewed by curation team. More than three unrelated individuals reported in the literature, ID is part of the phenotype. Publications support gene-disease association and rating of this gene to Green.
Created: 31 Oct 2018, 3:26 p.m.
Comment on publications: Added publication suggested by external reviewer. PMID: 30166628 is a recent publication on IRF2BPL-related phenotypes and reports on 11 unrelated individuals with de novo heterozygous truncating variants. Most individuals displayed complex neurological phenotypes, including delayed psychomotor development, variable Intellectual disability, developmental stagnation or cognitive decline preceded, accompanied or followed by the onset of seizures
Created: 31 Oct 2018, 3:24 p.m.
Green List (high evidence)
PMID: 30166628 is a new publication on the IRF2BPL-related phenotypes and reports on 11 unrelated individuals with de novo heterozygous truncating variants. The reported variants included 6 nonsense and 5 frameshift mutations. Most individuals displayed developmental stagnation or cognitive decline preceded, accompanied or followed by the onset of seizures. Although initial motor development was in most cases normal, mild speech delay was a feature in many individuals while 2 individuals presented with motor and speech delay prior to the onset of regression. In addition, among the 11 individuals, 3 displayed late onset regression (one at 5-6 years, and a further two at 10 and 17 years respectively). Onset of seizures may occur several years after onset of regression. As a result these individuals may be evaluated for their developmental delay and/or regression and the gene could be considered - apart from the epilepsy panel - also for the ID panel. In addition a previous publication (PMID 30057031), suggests a milder phenotype for individuals with missense variants, the latter presenting with developmental delay and seizures without the occurrence of regression. IRF2BPL is an intronless gene. The authors suggest that truncating variants escape nonsense mediated decay, with reverse transcription PCR from patient derived fibroblasts supporting the presence of a translated shorter protein.
Created: 5 Sep 2018, 1:56 a.m.
PMID 30057031 reports on 7 unrelated individuals, all with de novo SNVs in IRF2BPL. Individuals with stopgain SNVs displayed developmental regression, seizures, progressive ataxia and lack of coordination. The phenotype was milder in 2 subjects with missense variants and consisted of hypotonia, global developmental delay and seizures, without motor regression. One of the latter individuals had a diagnosis of autism spectrum disorder (ASD). Many individuals with either type of variant, were non-ambulatory/wheelchair bound and/or non-verbal. Almost all individuals suffered from epilepsy.
Functional analyses in flies were suggestive of a loss-of-function model for IRF2BPL-related disorders.
As the authors point out, individuals with missense and frameshift variants were previously reported by the DDD study [PMID 28135719 - individuals : DDD4K.03622, DDD4K.02435] as well as in a previous ASD study [PMID 25363768 - individuals : 13382 and 11480].
Created: 15 Aug 2018, 10:33 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Global developmental delay; Developmental regression; Seizures; Ataxia
Phenotypes for gene: IRF2BPL were changed from Global developmental delay; Developmental regression; Seizures; Ataxia to Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures; Global developmental delay, Developmental regression, Seizures, Ataxia
Gene: irf2bpl has been classified as Green List (High Evidence).
Publications for gene: IRF2BPL were set to 30057031; 28135719; 25363768
IRF2BPL was added to Intellectual disability panel. Sources: Literature
IRF2BPL was created by Konstantinos Varvagiannis
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).
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).
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.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
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 [email protected]
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.