Friday, July 7, 2023

IRF2BPL mutations

Inspired by a colleague's patient

Horovitz DDG, de Faria Domingues de Lima MA, Pires LC, Campos Araujo AQ, Vargas FR. Neurological Phenotypes of IRF2BPL Gene Variants: A Report of Four Novel Variants. J Cent Nerv Syst Dis. 2023 Jun 13;15:11795735231181467. doi: 10.1177/11795735231181467. PMID: 37346291; PMCID: PMC10280516.


IRF2BPL gene variants have recently been associated to developmental disability and epilepsy in children and movement disorders in adults. So far, only few cases have been reported; here we present four novel cases identified by exome sequencing, while investigating developmental delay, adult-onset cerebellar ataxia or regression.

Costa C, Oliver KL, Calvello C, Cameron JM, Imperatore V, Tonelli L, Colavito D, Franceschetti S, Canafoglia L, Berkovic SF, Prontera P. IRF2BPL: A new genotype for progressive myoclonus epilepsies. Epilepsia. 2023 Feb 21. doi: 10.1111/epi.17557. Epub ahead of print. PMID: 36810721.


The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.

Pisano S, Melis M, Figorilli M, Polizzi L, Rocchi L, Giglio S, Defazio G, Muroni A. Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature. Seizure. 2022 Jul;99:12-15. doi: 10.1016/j.seizure.2022.04.010. Epub 2022 Apr 18. PMID: 35525099.


Background: IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein.

Objective: To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis.

Methods: We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1).

Results: All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12).

Conclusions: Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

Shelkowitz E, Singh JK, Larson A, Elias ER. IRF2BPL gene mutation: Expanding on neurologic phenotypes. Am J Med Genet A. 2019 Nov;179(11):2263-2271. doi: 10.1002/ajmg.a.61328. Epub 2019 Aug 20. PMID: 31432588.


Heterozygous loss of function variants in the IRF2BPL are a newly described cause of neurodevelopmental disabilities and epilepsy. As of 2019, fewer than 20 patients have been described in the published literature. This article reports an additional case of a patient with a pathogenic IRF2BPL variant and offers a comprehensive review of the published cases of individuals with IRF2BPL variants, in order to help expand the phenotype. The patient has a history of infantile spasms evolving into drug-resistant epilepsy with underlying epileptic encephalopathy consistent with Lennox-Gastaut syndrome. While at the extreme end of the spectrum, his phenotype is consistent with those previously described. Our literature review highlights the wide range of phenotypes exhibited by those with diseases related to IRF2BPL gene variants. This article also briefly discusses other comorbidities seen in the patient and those previously reported. While the molecular underpinnings of the role of IRF2BPL gene in the central nervous system are newly established, the specifics of its effects elsewhere have yet to be delineated. Furthermore, its pathogenesis in other organ systems is not yet understood and could be of importance from a management perspective.

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