Abstract
Interferon regulatory factor 2 binding protein-like (IRF2BPL) is a single-exon gene that is ubiquitously expressed in various tissues, including the brain. IRF2BPL encodes a transcription factor with two zinc-finger domains that potentially downregulate WNT signaling in the nervous system. Pathogenic IRF2BPL variants have been reported to cause developmental delay, seizures, myoclonus epilepsies, autistic spectrum disorder, and other neurodevelopmental disorders. Exome sequencing of 10 patients with developmental delay and/or epilepsy from nine families revealed nine pathogenic IRF2BPL variants, of which eight were novel: five missense, one in-frame indel, and three truncating variants. Using reported pathogenic and benign variants, we highlight here several regions of IRF2BPL that deviate in the frequency of pathogenic and benign variants. This study of detailed clinical and genetic information shows that IRF2BPL missense and in-frame indel variants are often associated with seizures and developmental delay.
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References
Dissen GA, Lomniczi A, Heger S, Neff TL, Ojeda SR. Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates. Endocrinology. 2012;153:350–61.
Li C, Li P. Enhanced at puberty-1 (Eap1) expression critically regulates the onset of puberty independent of hypothalamic kiss1 expression. Cell Physiol Biochem. 2017;43:1402–12.
Marcogliese PC, Shashi V, Spillmann RC, Stong N, Rosenfeld JA, Koenig MK, et al. IRF2BPL is associated with neurological phenotypes. Am J Hum Genet. 2018;103:245–60.
Tran Mau-Them F, Guibaud L, Duplomb L, Keren B, Lindstrom K, Marey I, et al. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy. Genet Med. 2019;21:1008–14.
Costa C, Oliver KL, Calvello C, Cameron JM, Imperatore V, Tonelli L, et al. IRF2BPL: a new genotype for progressive myoclonus epilepsies. Epilepsia. 2023;64:e164–e69.
Sinha Ray S, Dutta D, Dennys C, Powers S, Roussel F, Lisowski P, et al. Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy. Cell Rep. 2022;41:111751.
Iwama K, Mizuguchi T, Takeshita E, Nakagawa E, Okazaki T, Nomura Y, et al. Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing. J Med Genet. 2019;56:396–407.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–89.
Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 2022;50:D439–D44.
Ginevrino M, Battini R, Nuovo S, Simonati A, Micalizzi A, Contaldo I, et al. A novel IRF2BPL truncating variant is associated with endolysosomal storage. Mol Biol Rep. 2020;47:711–14.
Antonelli F, Grieco G, Cavallieri F, Casella A, Valente EM. Adult onset familiar dystonia-plus syndrome: a novel presentation of IRF2BPL-associated neurodegeneration. Parkinsonism Relat Disord. 2022;94:22–24.
Ganos C, Zittel S, Hidding U, Funke C, Biskup S, Bhatia KP. IRF2BPL mutations cause autosomal dominant dystonia with anarthria, slow saccades and seizures. Parkinsonism Relat Disord. 2019;68:57–9.
Gardella E, Michelucci R, Christensen HM, Fenger CD, Reale C, Riguzzi P, et al. IRF2BPL as a novel causative gene for progressive myoclonus epilepsy. Epilepsia. 2023;64:e170–e76.
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;15:11795735231181467.
Li J, Gao K, Yan H, Xiangwei W, Liu N, Wang T, et al. Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation. Gene. 2019;700:168–75.
Mahdiannasser M, Rashidi-Nezhad A, Badv RS, Akrami SM. Exploring the genetic etiology of drug-resistant epilepsy: incorporation of exome sequencing into practice. Acta Neurol Belg. 2022;122:1457–68.
Pisano S, Melis M, Figorilli M, Polizzi L, Rocchi L, Giglio S, et al. Neurological phenomenology of the IRF2BPL mutation syndrome: analysis of a new case and systematic review of the literature. Seizure. 2022;99:12–5.
Prilop L, Buchert R, Woerz S, Gerloff C, Haack TB, Zittel S. IRF2BPL mutation causes nigrostriatal degeneration presenting with dystonia, spasticity and keratoconus. Parkinsonism Relat Disord. 2020;79:141–43.
Shelkowitz E, Singh JK, Larson A, Elias ER. IRF2BPL gene mutation: expanding on neurologic phenotypes. Am J Med Genet A. 2019;179:2263–71.
Skorvanek M, Dusek P, Rydzanicz M, Walczak A, Kosinska J, Kostrzewa G, et al. Neurodevelopmental disorder associated with IRF2BPL gene mutation: expanding the phenotype? Parkinsonism Relat Disord. 2019;62:239–41.
Spagnoli C, Rizzi S, Salerno GG, Frattini D, Fusco C. IRF2BPL gene variants: one new case. Am J Med Genet A. 2020;182:255–56.
van Kempen M, Kim SS, Tumescheit C, Mirdita M, Lee J, Gilchrist CLM, et al. Fast and accurate protein structure search with Foldseek. Nat Biotechnol. 2024;42:243–46.
Torene RI, Guillen Sacoto MJ, Millan F, Zhang Z, McGee S, Oetjens M, et al. Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases. Am J Hum Genet. 2024;111:70–81.
Keller MD, Pandey R, Li D, Glessner J, Tian L, Henrickson SE, et al. Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J Allergy Clin Immunol. 2016;138:544–50.e4.
Shihab HA, Gough J, Mort M, Cooper DN, Day IN, Gaunt TR. Ranking non-synonymous single nucleotide polymorphisms based on disease concepts. Hum Genom. 2014;8:11.
Cheng J, Novati G, Pan J, Bycroft C, Zemgulyte A, Applebaum T, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science. 2023;381:eadg7492.
Higashimori A, Dong Y, Zhang Y, Kang W, Nakatsu G, Ng SSM, et al. Forkhead box F2 suppresses gastric cancer through a Novel FOXF2-IRF2BPL-beta-catenin signaling axis. Cancer Res. 2018;78:1643–56.
Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015;134:97–109.
Acknowledgements
The authors thank the patients and their families for their cooperation in the present study. We also thank Ms. K. Takabe, Mr. T. Miyama, Ms. N. Watanabe, Ms. M. Sato, Mr. S. Nakamura, and Ms. S. Sugimoto at the Department of Human Genetics, Yokohama City University Graduate School of Medicine, for their technical assistance. We thank Catherine Perfect, MA (Cantab), from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript. This work was supported by AMED under grant numbers JP24ek0109674, JP24ek0109760, JP24ek0109617, JP24ek0109648 and JP24ek0109677 (NM); JSPS KAKENHI under grant numbers JP23K27520 (SM), JP23K27568 and JP23K18278 (TM), JP23K07229 (YU), JP23K15353 (NT), JP22K15901 (AF), JP20K16862 (KI), 24ek0109591 (MK) and JP24K02230 (NM); the Takeda Science Foundation (TM, NM), the Ministry of Health, Labor, and Welfare Research Program on Rare and Intractable Diseases under grant number JPMH23FC0201 (MK), The Ichiro Kanehara Foundation for the Promotion of Medical Science & Medical Care (SM).
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KI and NM designed the analyses, collected and interpreted the data, and wrote the manuscript. KI performed the bioinformatic analysis. TS and K Ogata performed structural analyses. KI, YU, M Sakamoto, YA, SO and KH performed the genetic investigation for patients. Clinical evaluation was performed by MK, RM, YI, K Ohashi, AH, NY, AW, CI, YS, SK, EN, M Sasaki, KS and SS. NT, EK, AF, MN, SM, HS, SI and TM interpreted the results, and critically reviewed the manuscript. all authors reviewed and approved the manuscript.
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Iwama, K., Kato, M., Uchiyama, Y. et al. Clinical and genetic spectrum of patients with IRF2BPL syndrome. J Hum Genet 70, 181–188 (2025). https://doi.org/10.1038/s10038-025-01316-2
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DOI: https://doi.org/10.1038/s10038-025-01316-2
