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Genetic epilepsy syndromes

Gene: IRF2BPL

Green List (high evidence)

IRF2BPL (interferon regulatory factor 2 binding protein like)
EnsemblGeneIds (GRCh38): ENSG00000119669
EnsemblGeneIds (GRCh37): ENSG00000119669
OMIM: 611720, Gene2Phenotype
IRF2BPL is in 6 panels

5 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

AD neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS). Marcogliese et al, 2018 - 7 unrelated patients aged from 2.5 to 43years with a neurodevelopmental disorder. Additional features included variable types of seizures in all individuals - 5 nonsense and 2 missense (phenotype milder), 5/7 confirmed de novo no parents for other 2. Expression studies done. Tran Mau Them, 2018 - 11 unrelated individuals - epilepsy seen in 7/11 patients all individuals had de novo nonsense or fs mutations.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, 618088

Publications

Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. More than 10 truncating variants identified in unrelated cases.
Created: 26 Sep 2018, 9:14 a.m.

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Further 11 unrelated individuals with truncating de novo variants in this gene reported.
Created: 3 Sep 2018, 9:58 a.m.
7 unrelated individuals reported with de novo variants in this gene and complex neurological phenotypes, including seizures.
Created: 16 Aug 2018, 12:57 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

Variants in this GENE are reported as part of current diagnostic practice

Konstantinos Varvagiannis (Other)

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, 1:58 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] (although the latter is not relevant to the phenotype of epilepsy).
Created: 15 Aug 2018, 10:36 a.m.

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

Phenotypes
Global developmental delay; Developmental regression; Seizures; Ataxia

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures 618088
OMIM
611720
Clinvar variants
Variants in IRF2BPL
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to IRF2BPL.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to IRF2BPL.

11 Dec 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Konstantinos Varvagiannis: PMID 30057031 reports on 7 unr

26 Sep 2018, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

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 618088

26 Sep 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: irf2bpl has been classified as Green List (High Evidence).

26 Sep 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: irf2bpl has been classified as Green List (High Evidence).

15 Aug 2018, Gel status: 0

Added New Source

Konstantinos Varvagiannis (Other)

IRF2BPL was added to Genetic Epilepsy Syndromes panel. Sources: Literature

15 Aug 2018, Gel status: 0

Created

Konstantinos Varvagiannis (Other)

IRF2BPL was created by Konstantinos Varvagiannis