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Novel IRF2BPL gene mutation manifesting as a broad spectrum of neurological disorders: a case report
  1. Wardah Javed Khan1,2,
  2. Hamza Maqsood3 and
  3. Shifa Younus3
  1. 1Northwest School of Medicine, Peshawar, Pakistan
  2. 2Khyber Girls Medical College, Peshawar, Pakistan
  3. 3Neurology, Nishtar Medical College and Hospital, Multan, Punjab, Pakistan
  1. Correspondence to Dr Hamza Maqsood; hamzamaqsood381{at}


Background IRF2BPL (interferon regulatory factor 2-binding protein-like) gene is an intronless gene present ubiquitously in the human body, including the brain. Pathogenic variants lead to neurodegeneration and present with phenotypic features of a neurological disorder, including dyslexia, dyscalculia, epilepsy, dystonia, neurodevelopmental regression, loss of motor skills and cerebellar ataxia.

Case We present a case of a 9-year-old boy who was brought to the emergency department with generalised tonic-clonic seizures and mild hypotonia. A history included neurological regression. After insignificant lab and imaging results, the patient underwent genetic testing, revealing a novel pathogenic mutation in the IRF2BPL gene (heterozygous variant), which had never been reported in the literature before. An autosomal dominant loss of function mutation was demonstrated, denoting in DNA as NM_0 24 496 c.911 C>T, which results in premature protein termination (p.Glu494).

Conclusion Our case highlights the importance of early recognition of the neurological symptoms associated with various IRF2BPL gene mutations so that a timely multidisciplinary management approach can be provided.

  • EEG

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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IRF2BPL is an intronless gene encoding for interferon regulatory factor 2-binding protein-like protein.1 2 The zinc finger/RING finger protein acts as a transcriptional modulator and aids in proteasome degradation in gastric cancer by functioning as an E3 ubiquitin ligase that targets B-catenin.1 A study of a patient with a truncated variant of IRF2BPL also demonstrated cells with features similar to and suggestive of a lysosomal storage disorder.3 Ubiquitous expression of the IRF2BPL is noted in various body cells, including the central nervous system.3 4 Similarly, a recent study by Marcogliese et al described that along with neurological abnormalities, loss of IRF2BPL increases wnt1 transcription and downstream signalling. WNT1 is also elevated in astrocytes produced by patients, and neurological characteristics are suppressed by WNT pharmacological suppression.5

Pathogenic variants in this recently described gene cause neurodegeneration, leading to phenotypic features of a neurological disorder, including epilepsy, neurodevelopmental regression, loss of motor skills and cerebellar ataxia.6 Overexpression or complete gene loss may be lethal, while a partial knockdown leads to central nervous system degeneration.7 As of 2021, IRF2BPL gene mutation was only highlighted in 27 patients in the published research literature, making it a distinct pathogenic mutation to study.2 We present a novel case of a homozygous variant of the IRF2BPL gene, which has never been reported in the literature before.

Case presentation

A 9-year-old Asian boy was brought to the emergency department with generalised tonic-clonic seizures 1 hour ago. The patient experienced both urinary and faecal incontinence, followed by loss of consciousness. The patient had headaches after awakening. There was no history of trauma, fever, brain surgery or vomiting. Other neurological problems include the inability to maintain posture in a sitting position that appeared at 3 years of age and difficulty swallowing from 4 years of age, which progressed gradually to the extent that the patient had to be put on a nasogastric feeding tube. In addition, the patient’s mother also mentioned that the patient has learning disabilities, including dyslexia and dyscalculia, which started when he was 7 years old. At this age, he was diagnosed with cerebral palsy and was treated accordingly with symptomatic management. The boy was delivered via a normal spontaneous vaginal delivery. The patient has no significant family history of medical problems and has a sister with no medical problems. In addition, the patient has no drug abuse history or prior medical treatment history.

General physical examination was insignificant except for central nervous system findings. The patient was alert and oriented in time and space but with scanned speech. The power was 3/4 in all extremities, and mild hypotonia was noted. The neurological examination was done 1 hour after the presentation when the patient was postictal. His reflexes were brisk, with a positive ankle clonus and positive Babinski sign. Mini-Mental State Examination was mildly affected and was 23/30.

The patient underwent laboratory testing, including a complete blood count, liver function test, renal function tests and urine toxicology. Radiological imaging included CT and MRI scans, both of which were normal. A psychiatric evaluation was also done. On electroencephalogram (EEG), generalised 10 Hz polyspikes were seen during the tonic phase, followed by a 1 Hz spike-wave pattern reflecting the clonic phase of the patient’s generalised tonic-clonic seizures (figure 1).

Figure 1

An ictal electroencephalogram (EEG) showing 1 Hz spike-wave pattern denoted as clonic phase and 10 Hz polyspike waves denoted as tonic phase of a generalised tonic-clonic seizure.

At this stage, the differentials included inherited metabolic and genetic syndromes like Zellweger Syndrome, mitochondrial diseases, lysosomal storage diseases and neuropsychiatric conditions like Rett Syndrome. We suspected a genetic or metabolic condition based on neurological symptoms, EEG findings and the disease’s progressive nature. Before this presentation, the patient was having other neurological problems, which were attributed to cerebral palsy. But when evaluated comprehensively, we decided to go for a genetic evaluation. The patient was referred for genetic testing based on extensive neuropsychiatric disorder history. Genetic testing revealed an autosomal dominant loss of function mutation, denoting in DNA as NM_0 24 496 c.911 C>T, which results in premature protein termination (p.Glu494). Based on ACMG criteria, the mutation was pathogenic and de novo. There was no artefact or deletion in the alternate allele. No additional variants were identified that could be the reason for neurological presentation.

Symptomatic multidisciplinary management was started that included antiseizure medication (sodium valproate 250 mg) and multivitamin supplementation. He responded well to this medication regimen. The patient was also provided speech and language therapy, and genetic counselling was provided to the child’s parents.


The role of the IRF2BPl gene, encoding for the interferon regulatory factor 2 binding like protein, in Mendelian disease was first established by Marcogliese et al.8 9 In 2000, IRF2BPL was mapped to the 14q24.3 chromosome.2 The ClinVar ID for IRF2BPL gene is 1 707 441 and genome reference consortium (GRC) build IDs are GRCh37 and GRCh38. Although the recently studied gene’s function is still not completely known, it was previously known as enhanced at puberty protein 1 (EAP1) and thought to contribute to the development of puberty.2 8 10 Recent studies now suggest IRF2BPL possibly plays a role in the development and homeostasis of the central nervous system also.2 Interestingly, in support of its function, the ubiquitin–proteasome system has been described in the nucleus, where IRBF2BPL proteins are also localised.11 In addition, various body cells show ubiquitous expression of the IRF2BPL, including the central nervous system.2 3

The IRF2BPL gene is highly intolerant to variation. Complete gene loss is lethal in early neuronal development, while partial knockdown is consistent with neurodegeneration and neurodevelopmental disabilities.2 7 8 The heterozygous variant IRF2BPL found in our patient does not prove to be lethal but delineates the phenotype of a broad spectrum of neurological disorders. This suggests that an intact gene is required for proper neuronal development, functioning and maintenance. In our case, a broader spectrum of neurological disorders such as regression, neurodevelopmental delay and seizures from a significant time period and no obvious underlying cause led us to order genetic testing.

Pisano et al, in their case study and systematic review of literature, concluded that all patients studied exhibited similar neurological symptoms of developmental delay/regression, mainly epilepsy, ataxia, spasticity, dystonia and ocular disturbances, with insignificant involvement of other organs in the body, suggesting the IRF2BPL mutation syndrome is highly specific to the central nervous system. The case study of a female in her 20s with the pathogenic variant of the IRF2BPL had developmental delay, myoclonic epilepsy, speech disturbances and dystonia. Similar to our patients, psychomotor development initially appeared normal, and symptoms of developmental delay or neurological regression did not show up until years after birth. Learning disabilities, including dyslexia and dyscalculia, started at 7.2

The study by Marcogliese et al further contributed to and strengthened the clinical diversity of IRF2BPL gene mutation and showed similarities with our patient’s symptoms. In the study of five patients with neurological regression, dominant de novo heterozygous variations in IRF2BPL were studied. The age of onset of motor regression in these patients ranged from 2.5 to 10 years of age, with the patients losing gross motor and oromotor skills. These previously normally developed patients became wheelchair-bound, had an unsteady gait, and exhibited progressive dysphagia and silent aspiration, eventually requiring tube feedings.8 Our study strengthens the studies on the phenotypic expansion of mutations occurring in the IRF2BPL gene. Neurological disorders of these patients included seizures in all patients, with some having ataxia, dystonia, hypotonia and/or choreoathetosis, similar to our patient, who presented with generalised tonic-clonic seizures and also exhibited mild hypotonia.8

In a study by Tran Mau-Them et al, all patients had de novo heterozygous truncating variants in the IRF2BPL gene, including nonsense and frameshift mutations.10 They all shared a similar phenotypic spectrum of neurodevelopmental disorder. Similar to our patient, the initial psychomotor development was normal, with neurological regression in most patients. Seizures presented early in life were apparent from ages 6 months to 26 years and included infantile spasms and tonic-clonic seizures with non-specific patterns on EEG and myoclonus. EEG showed multifocal polyspikes and waves, consistent with our patient’s EEG.10

In a Chinese case report by Yang et al, a young boy with a nonsense variant in IRF2BPL presented with rapid progressive dysarthria and dystonia. Although the patient did not experience epilepsy, as did our patient, the phenotypic spectrum of the disorder exhibited similarities. He had developed normally until the age of 8 years when he experienced motor regression with abnormal posture, dysphagia, dystonia and drooling, similar to our patient but without seizures.7

Studies on the gene IRF2BPL have been described as a novel cause of neurodevelopmental disorders characterised by neurological regression, epilepsy, dysphagia, dystonia, cerebellar symptoms and pyramidal signs. An additional study now also suggests that progressive myoclonus epilepsy can be an additional phenotype adding to the spectrum of disorders caused by mutations in the IRF2BPL gene.12 This suggests there is still much unknown about the gene, and future studies are encouraged to provide further insight into this topic of study.

In summary, a mutation in the IRF2BPL gene is consistent with variable central nervous system anomalies. Exome and genome sequencing have allowed for the identification of gene variants, including de novo heterozygous mutations consisting of nonsense, missense and frameshift mutations.10 In addition to other variants studied, our case supports the novel heterozygous variant in the gene, characterised by NM_0 24 496 c.911 C>T mutation, which results in premature protein termination (p.Glu494). Further, it delineates the phenotypic spectrum of the disorder characterised by neurological symptoms and regression. Our case strengthens knowledge and research on this recently studied gene and provides indications to improve recognition of its phenotypic expression and facilitate clinical diagnosis.


Our case study and the literature reviewed here highlight the importance of recognising the neurological symptoms associated with various IRF2BPL gene mutations, as in our case, the patient was found to have a novel pathogenic mutation denoted at DNA as c.911 C>T. These include the delayed onset of symptoms, neurological regression,and the phenotypic variability observed in different patients.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

Ethics statements

Patient consent for publication


The authors thank their patient and his family for their support and permission to publish this

case study.



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  • Contributors WJK was involved in the clinical care of the patient. The initial draft of the manuscript was prepared by WJK and HM, which was edited and proofread by HM and SY. All authors were involved in the review of the literature, revising the manuscript and approving the final draft.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.