IRF2BPL gene mutation: Expanding on neurologic phenotypes

Abstract

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

IRF2BPL gene variants: One new case

“…The gene product is a zinc finger/RING finger protein acting as a transcriptional modulator (Marcogliese et al, 2018). Therefore we were very interested in the recently published paper describing one additional patient with Lennox-Gastaut syndrome, hypotonia, retinal dysfunction and gastrointestinal dysmotility (Shelkowitz, Singh, Larson, & Elias, 2019), and also providing a review of all described patients, highlighting a wide range of neurological presentations, with some core elements: childhood-onset epilepsy with developmental regression (impacting more on language), cerebral atrophy in the long-term follow-up, hypotonia and hyperreflexia.…”

“…The presence of gastrointestinal symptoms has been highlighted in different patients (Shelkowitz et al, 2019), and interpreted as possibly related to IRF2BPL gene products extra-neural location (The Gtex Consortium, 2013).…”

“…He is also affected by episodes of instability with frequent falls and myoclonus of non-epileptic origin. From the literature EEG and epilepsy phenotype seems to be unspecific, but myoclonic and tonic-clonic seizures recur in multiple patients (Marcogliese et al, 2018;Shelkowitz et al, 2019;Tran Mau-Them et al, 2019), while photosensitivity has been documented once (Marcogliese et al, 2018).…”

Do variants in IRF2BPL cause both neurological disorders and keratoconus 8?

“…We identified one additional report of a patient with IRF2BPL-related diseases who had reduced visual acuity but where ophthalmological evaluation revealed normal optic disks and electroretinogram [10]. In contrast, in another previous report on a 10-year old patient with IRF2BPL variants and poor vision [7], electroretinogram demonstrated a rod-cone dysfunction as in retinal degeneration. This might be significant because there may be a biological link between keratoconus and retinal disease; non-syndromic early-onset types of retinal degeneration (Leber congenital amaurosis 1, 4 and 8 [12][13][14]) have in a few reports been associated with keratoconus.…”

“…1. Genomic location on chromosome 14 that includes the locus for keratoconus type 8 (KTCN8) as determined by Lišková et al [5], and the IRF2BL gene, in which four de novo truncating variants have been described in independent patients with neurological disease and keratoconus [1][2][3], reduced visual acuity [10], or retinal degeneration [7]. The highest LOD scores (3.58) in the keratoconus 8 families were obtained for rs1074501 and rs755212 [5].…”