De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Mau-Them, Frédéric Tran; Guibaud, Laurent; Duplomb, Laurence; Keren, Boris; Lindstrom, Kristin; Marey, Isabelle; Mochel, Fanny; Boogaard, M. J. van den; Oegema, Renske; Nava, Caroline; Masurel, Alice; Jouan, Thibaud; Jansen, Floor E.; Au, Margaret G.; Chen, Agnes H.; Cho, M.; Duffourd, Yannis; Lozier, Ekaterina; Коновалов, Ф. А.; Sharkov, Artem; Korostelev, Sergey; Urteaga, Benoit; Dickson, PI; Vera, M. Concepcion Nuñez Pardo de; Martínez‐Agosto, Julian A.; Begemann, Anaïs; Zweier, Christiane; Schmitt‐Mechelke, Thomas; Rauch, Anita; Philippe, Christophe; Gassen, Koen van; Nelson, Stanley F.; Graham, John M.; Friedman, Jennifer; Faivre, Laurence; Lin, Henry J.; Thauvin‐Robinet, Christel; Vitobello, Antonio

doi:10.1038/s41436-018-0143-0

Cited by 41 publications

(75 citation statements)

References 20 publications

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“…The remaining patients were still living. At the time of publication of the case reports (Macrogliese et al, ; Skorvanek et al, ; Tran Mau‐Them et al, ), the median age of patients was 10.5 years with a range of 17 months to 48 years.…”

Section: Resultsmentioning

confidence: 99%

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IRF2BPL gene mutation: Expanding on neurologic phenotypes

Shelkowitz

Singh

Larson

et al. 2019

American J of Med Genetics Pt A

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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. K E Y W O R D Sdevelopmental regression, epilepsy, intellectual disability, IRF2BPL gene mutation

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Section: Resultsmentioning

confidence: 99%

“…The first clinical descriptions of individuals with IRF2BPL variants were published in 2018. While the phenotype is varied, it has been associated with developmental regression in childhood as well as epilepsy (Macrogliese et al, ; Skorvanek et al, ; Tran Mau‐Them et al, ).…”

Section: Introductionmentioning

confidence: 99%

IRF2BPL gene mutation: Expanding on neurologic phenotypes

Shelkowitz

Singh

Larson

et al. 2019

American J of Med Genetics Pt A

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“…For example, in the first half of 2019, two more genes (RYR2 and IRF2BL) have already been reported to be associated with epilepsy. 3,4 While new genes continue to be reported, several genes are repeatedly identified in broad epilepsy studies (►Table 2). Most of the studies which have looked at potential single gene variants causing epilepsy have been carried out in people with epileptic encephalopathies, often with an early age of onset and normal imaging findings.…”

Section: What Are the Major Genetic Epilepsies?mentioning

confidence: 99%

Genetic Testing in Epilepsy

Ritter

Holland

2020

Semin Neurol

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Because of next-generation sequencing and the discovery of many new causative genes, genetic testing in epilepsy patients has become widespread. Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into syndromic disorders (i.e., chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling. Here, we review the available genetic testing, reasons to pursue genetic testing, common genetic causes of epilepsy, the data behind what patients are found to have genetic epilepsies based on current testing, and discussing these results with patients. We propose an algorithm for testing patients with epilepsy to maximize yield and limit costs based on their phenotype (including electroencephalography and magnetic resonance imaging findings), age of seizure onset, and presence of other neurologic comorbidities. Being able to discern which type of genetic testing to order, using that information to give targeted and cost-effective patient care, and interpreting results accurately will be a crucial skill for the modern neurologist.

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“…Since then, mutations in the KMT2B gene have been added to this list and indeed, two of the patients we previously reported (cases 15 and 20) 1 were subsequently found to harbor pathogenic mutations in this gene. Here, we wish to highlight a novel genetic etiology, namely mutations in the IRF2BPL gene, recently reported to cause a broad phenotypic range of neurological syndromes [2][3][4] , with a particular focus on the syndromic association of dystonia with anarthria/aphonia.…”

mentioning

confidence: 99%