“…Even though pathogenic variants have been reported throughout the gene, the majority are localized in the polyglutamine tract or before the first PEST sequence of the gene. 1,2,[6][7][8][9][10][11][12][13] A PEST sequence is a proline, glutamate, serine, threonine rich region that serves as signal for rapid proteolytic degradation. 14 There are 3 regions predicted to be PEST motifis in this gene (positions 201-213, 331-342 and 545-559).…”
Section: Discussionmentioning
confidence: 99%
“…Whether this region represents a cluster for adult-life presentations of the disease is still not known.Figure 4.Schematic representation of IRF2BPL gene and variants reported. 1,2,7-11,13,15-22 Bold text represents variants described in this study.…”
Section: Discussionmentioning
confidence: 99%
“… Schematic representation of IRF2BPL gene and variants reported. 1 , 2 , 7 - 11 , 13 , 15 - 22 Bold text represents variants described in this study. …”
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.
“…Even though pathogenic variants have been reported throughout the gene, the majority are localized in the polyglutamine tract or before the first PEST sequence of the gene. 1,2,[6][7][8][9][10][11][12][13] A PEST sequence is a proline, glutamate, serine, threonine rich region that serves as signal for rapid proteolytic degradation. 14 There are 3 regions predicted to be PEST motifis in this gene (positions 201-213, 331-342 and 545-559).…”
Section: Discussionmentioning
confidence: 99%
“…Whether this region represents a cluster for adult-life presentations of the disease is still not known.Figure 4.Schematic representation of IRF2BPL gene and variants reported. 1,2,7-11,13,15-22 Bold text represents variants described in this study.…”
Section: Discussionmentioning
confidence: 99%
“… Schematic representation of IRF2BPL gene and variants reported. 1 , 2 , 7 - 11 , 13 , 15 - 22 Bold text represents variants described in this study. …”
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.
Background
Pathogenic variants of the IRF2BPL gene have been reported to cause neurodevelopmental disorders; however, studies focused on IRF2BPL in zebrafish are limited.
Results
We reported three probands diagnosed with developmental delay and epilepsy and investigated the role of IRF2BPL in neurodevelopmental disorders in zebrafish. The clinical and genetic characteristics of three patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS) were collected. Three de novo variants (NM_024496.4: c.1171 C > T, p.Arg391Cys; c.1157 C > T, p.Thr386Met; and c.273_307del, p.Ala92Thrfs*29) were detected and classified as pathogenic or likely pathogenic according to ACMG guidelines. Zebrafish crispants with disruption of the ortholog gene irf2bpl demonstrated a reduced body length and spontaneous ictal-like and interictal-like discharges in an electrophysiology study. After their spasms were controlled, they gain some development improvements.
Conclusion
We contribute two new pathogenic variants for IRF2BPL related developmental epileptic disorder which provided evidences for genetic counseling. In zebrafish model, we for the first time confirm that disruption of irf2bpl could introduce spontaneous electrographic seizures which mimics key phenotypes in human patients. Our follow-up results suggest that timely cessation of spasmodic seizures can improve the patient’s neurodevelopment.
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