RNU4-2 / ReNU Syndrome Scientific Publications

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2026

  • Recurrent RNU4-2 n.64_65insT variant in ReNU syndrome identified in exome-negative cases

    Brain and Development | July 2026

    Takuya Hiraide, Kenji Shimizu, Taiju Hayashi, et al. 2026. “Recurrent RNU4-2 n.64_65insT variant in ReNU syndrome identified in exome-negative cases” Brain and Development, Volume 48, Issue 4, 2026, 104570, ISSN 0387-7604, https://doi.org/10.1016/j.braindev.2026.104570.

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  • Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language

    National Institutes of Health (NIH) Genetic and Rare Diseases (GARD) Information Center | July 2026

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  • RNU4-2–Related Autosomal Dominant Neurodevelopmental Disorder

    GeneReviews® | May 2026

    Barbosa M, Chopra M, Turro E, Valenzuela Palafoll I. RNU4-2–Related Autosomal Dominant Neurodevelopmental Disorder. 2026 May 26. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 42190036.

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  • Summary of the Inaugural ReNU Hope Conference and Scientific Symposium, July 23–25, 2025, Long Island, New York

    American Journal of Medical Genetics Part A | February 2026

    Crocker, K., J. O’Toole, L. Pearse, et al. 2026. “ Summary of the Inaugural ReNU Hope Conference and Scientific Symposium, July 23–25, 2025, Long Island, New York.” American Journal of Medical Genetics Part A 1–7. https://doi.org/10.1002/ajmg.a.70098.

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    RNU4-2 Global Map

  • De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa

    Nature Genetics | January 2026.

    Quinodoz, M., Rodenburg, K., Cvackova, Z. et al. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat Genet 58, 169–179 (2026). https://doi.org/10.1038/s41588-025-02451-4

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    Diagram illustrating RNA gene transcription and processing, showing noncoding RNA gene, snRNA genes, and RNU6 paralogs, the formation of snRNPs, dual and tri-snRNP complexes, and their roles in retinitis pigmentosa and neurodevelopmental disorder.

2025

  • Prenatal Evaluation of RNU4-2 Variants in Fetuses With Central Nervous System Anomalies

    America Journal of Medical Genetics | December 2025.

    Chen Y, Gao L, Han X, et al. Prenatal Evaluation of RNU4-2 Variants in Fetuses With Central Nervous System Anomalies. Am J Med Genet C Semin Med Genet. 2025 Dec 25. doi: 10.1002/ajmgc.70002. Epub ahead of print. PMID: 41449851.

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    Diagram illustrating the genetic and developmental process related to a specific disease. The image shows molecular structures, a human brain, a fetus, a DNA double helix with a magnified section revealing genetic code, and a flowchart indicating diagnostic outcomes, including resolved and excluded cases.

  • ReNU Syndrome due to a de novo RNU4-2 Variant as a Novel Genetic Cause of Proteinuria

    Kidney Medicine | December 2025

    William Morello, Greta Armaroli, Donatella Milani, et al. ReNU Syndrome due to a de novo RNU4-2 Variant as a Novel Genetic Cause of Proteinuria, Kidney Medicine, Volume 8, Issue 2, 2026, 101202, ISSN 2590-0595, https://doi.org/10.1016/j.xkme.2025.101202.

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    Diagram depicting a girl with a DNA strand labeled RNU4-2 and a kidney, illustrating minimal change disease and proteinuria, with a chart indicating stable kidney function over time.

  • Small nuclear RNA genes in Mendelian disorders

    Nature Genetics | December 2025

    Antonarakis, S. E. Small nuclear RNA genes in Mendelian disorders. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02440-7

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    Diagram illustrating how Pseudogenes are transcribed into pre-mRNA, modified into snRNA, combined with protein subunits to form snRNPs, which then assemble into spliceosomes. The spliceosomes impact neurodevelopmental delay, developmental abnormalities, and retinal pigmentosa.

  • Reanalysis of Undiagnosed Neurodevelopmental Disorder Cases: From RNU4-2 Variants to Clinical Phenotypes

    Neurology Genetics | October 2025

    Di Letto, P., De Leonibus, C., Palmieri, et al. (2025). Reanalysis of undiagnosed neurodevelopmental disorder cases: From RNU4-2 variants to clinical phenotypes. Neurology: Genetics, 11(6), e200312. https://doi.org/10.1212/NXG.0000000000200312

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    Diagram showing a 5-year-old girl with recognizable facial features, microcephaly, and hypotonia, alongside genetic elements including a DNA sequence with a mutation in the RNU4-2 gene, which is linked to delayed development and brain activity issues. The image depicts genetic investigations and a cell with DNA strands.

  • A Rare Case of Osteosarcoma in an Individual with the Recurrent n.64_65insT Variant in the RNU4-2 Gene

    Case Reports in Clinical Medicine | September 2025

    Haas, H. , Strom, S. , Kesari, A. , et al. (2025) A Rare Case of Osteosarcoma in an Individual with the Recurrent n.64_65insT Variant in the RNU4-2 Gene. Case Reports in Clinical Medicine, 14, 504-508. doi: 10.4236/crcm.2025.149064

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    Diagram showing the RNU4-2 gene variant's link to osteosarcoma, with genetic sequences, a human silhouette, a bone, and a timeline indicating 21 and 5-year markers.

  • ReNU syndrome - a newly described prevalent neurodevelopmental disorder: first case in the Czech Republic

    Česko-Slovenská Pediatrie | July 2025

    Slabá K, Pokorná P, Koželková K, et al.. ReNU syndrome - a newly described prevalent neurodevelopmental disorder: first case in the Czech Republic. Ces-slov Pediat. 2025;80(4):177-181. doi: 10.55095/CSPediatrie2025/029.goes here

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    Infographic showing genetic sequencing process for diagnosing rare neurodevelopmental disorders. It features a child, genetic data, and mentions the RNU4-2 gene mutation linked to ReNU syndrome, with data on prevalence and sequencing methods

  • Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption

    Nature Genetics | May 2025

    Nava, C., Cogne, B., Santini, A. et al. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. Nat Genet 57, 1374–1388 (2025). https://doi.org/10.1038/s41588-025-02184-4

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    Diagram illustrating genetic variations and their impact on methylation patterns and clinical severity, involving RNU4-2 gene, splice site mutations, epigenetic patterns, and variants in RNU5B-1 and RNU5A-1 genes.

  • Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders

    medRxiv | April 2025

    De Jonghe J, Kim HC, Adedeji A, et al. Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders. medRxiv. 2025 Apr 10:2025.04.08.25325442. doi: 10.1101/2025.04.08.25325442

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    Diagram showing the genetic mutation effects such as ReNU syndrome, ReNU syndrome variants, and NDD, with a graph comparing

  • Expanding the mutational spectrum of ReNU syndrome: insights into 5’ Stem-loop variants

    European Journal of Human Genetics | February 2025

    Bruselles A, Mancini C, Chiriatti L, et al. Expanding the mutational spectrum of ReNU syndrome: insights into 5' Stem-loop variants. Eur J Hum Genet. 2025 Apr;33(4):432-440. doi: 10.1038/s41431-025-01820-1. Epub 2025 Feb 26. PMID: 40011755; PMCID: PMC11986017.

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2024

  • Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome

    Genetics in Medicine | October 2024

    Valenzuela, Irene et al. Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome, Genetics in Medicine, Volume 26, Issue 12, 101288.

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    ReNU recognizable facial gestalt with dysmorphic craniofacial features: deep-set eyes with epicanthus; wide nasal bridge, upturned nose; large or cupped ears; full lips downturned corners; high-arched palate; drool, dental anomalies

  • ReNU syndrome – a newly discovered prevalent neurodevelopmental disorder

    Trends in Genetics | October 2024.

    Burns VF, Radford EJ. ReNU syndrome - a newly discovered prevalent neurodevelopmental disorder. Trends Genet. 2024;40(11):914-916. 10.1016/j.tig.2024.09.005

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    Genetic testing process for boy with craniofacial dysmorphism. It shows the use of whole genome sequencing and targeted panels to identify pathogenic RNU4-2 gene variants linked to ReNU syndrome, highlighting need for WGS or targeted panels

  • De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

    Nature | July 2024.

    Chen, Y., Dawes, R., Kim, H.C. et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature 632, 832–840 (2024). https://doi.org/10.1038/s41586-024-07773-7.

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    Diagram illustrating the process of U4/U6 snRNA in splicing, including zones showing genetic encoding, duplex formation, spliceosome assembly, disruption and NDD consequences, with related molecular structures and processes.

  • Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder

    Clinical Genetics | June 2024

    Schot R, Ferraro F, Geeven G, Diderich KEM, Barakat TS. Re-analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an RNU4-2 related neurodevelopmental disorder. Clin Genet. 2024 Oct;106(4):512-517. doi: 10.1111/cge.14574. Epub 2024 Jun 11. PMID: 38859706.

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    Diagram of a five-year-old girl with recognizable facial features showing hypotonia and microcephaly, with a close-up of a DNA sequence highlighting a T nucleotide, and a representation of the RNU4-2 gene with associated genetic information, indicating delayed development, brain activity issues, and extensive previous failed genetic investigations.

  • The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder

    Pediatric Neurology | June 2024

    Barbour K, Bainbridge MN, Wigby K, et al. The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder. Pediatr Neurol. 2024 Dec; 161:188-193. doi: 10.1016/j.pediatrneurol. 2024.09.015

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  • Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders

    Nature Medicine | May 2024.

    Greene, D., Thys, C., Berry, I.R. et al. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders. Nat Med 30, 2165–2169 (2024). https://doi.org/10.1038/s41591-024-03085-5

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2026

  • Nakano Y, Suzuki H, Kuroda Y, et al. Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening iScience. 2026.

    View article (DOI) PMID: 42502410

  • Hiraide T, Shimizu K, Hayashi T, et al. Recurrent RNU4-2 n.64_65insT variant in ReNU syndrome identified in exome-negative cases Brain & Development. 2026.

    View article (DOI) PMID: 42419151

  • Rius R, Blakes AJM, Chen Y, et al. Author Correction: Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes Nature Genetics. 2026.

    View article (DOI) PMID: 42151417

  • Hussain JM, Ilyas L, Amir A, et al. ReNU Syndrome and the RNU4-2 Mutation: A Missed Cause of Childhood Neurodevelopmental Delay (review) Journal of Mother and Child. 2026.

    View article (DOI) PMID: 42285908

  • Brownstein CA, Madden JA, Shao W, et al. Multimodal Sequencing and Reanalysis Approaches to End the Diagnostic Odyssey of Individuals with Suspected Rare Monogenic Diseases Genes. 2026.

    View article (DOI) PMID: 42353806

  • van der Laan L, Luijckx A, Lo-A-Njoe S, et al. Episignature-based modelled first-tier diagnostic approach in the Dutch Caribbean: advancing equal care through epigenetic classification Frontiers in Genetics. 2026.

    View article (DOI) PMID: 42238820

  • Stemerdink M, Capasso D, Cicekdal MB. A new era for the dark genome Trends in Genetics. 2026.

    View article (DOI) PMID: 41974596

  • De Jonghe J, Kim HC, Adedeji A, et al. Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders Nature. 2026.

    View article (DOI) PMID: 41951737

  • Rius R, Blakes AJM, Chen Y, et al. Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes Nature Genetics. 2026.

    View article (DOI) PMID: 41951959

  • Greene D, Mendez R, Lees J, et al. Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder Nature Genetics. 2026.

    View article (DOI) PMID: 41912932

  • Leitão E, Santini A, Cogne B, et al. Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies Nature Genetics. 2026.

    View article (DOI) PMID: 41912934

  • Abaji M, Gerard B, Nasca L, et al. First Identification of a Heterozygous RNU4-2 and RNU4-1 Deletion Associated With Fetal Urogenital and Anorectal Malformations Prenatal Diagnosis. 2026.

    View article (DOI) PMID: 41862411

  • Hong J, Lee S, Kim SY, et al. Exploring the Impact of RNU4-2 Defects on Neurodevelopmental Disorders in a Korean Population Clinical Genetics. 2026.

    View article (DOI) PMID: 41731653

  • Crocker K, O'Toole J, Pearse L, et al. Summary of the Inaugural ReNU Hope Conference and Scientific Symposium, July 23-25, 2025, Long Island, New York AJMG Part A. 2026.

    View article (DOI) PMID: 41714173

  • Ajmone PF, Rigamonti C, Brasca F, et al. Longitudinal Behavior Phenotype Hallmarks in RNU4-2 Syndrome: Implications for Clinical Management AJMG Part B: Neuropsychiatric Genetics. 2026.

    View article (DOI) PMID: 41681065

  • Saleem Z, Hussain JM, Siddiqui QU, et al. Correspondence on "Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2" by Valenzuela et al. Genetics in Medicine. 2026.

    View article (DOI) PMID: 41574591

  • Valenzuela I, Codina-Solà M, Tizzano EF. Response to Saleem et al. Genetics in Medicine. 2026.

    View article (DOI) PMID: 41574592

  • Mastrangelo M, Tolve M, Valenzuela I, et al. Epilepsy phenotypes of ReNU syndrome: Novel insights from a European multicentre retrospective cohort study Seizure. 2026.

    View article (DOI) PMID: 41570780

  • Quinodoz M, Rodenburg K, Cvackova Z, et al. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa Nature Genetics. 2026.

    View article (DOI) PMID: 41513982

2025

  • Chen Y, Gao L, Han X, et al. Prenatal Evaluation of RNU4-2 Variants in Fetuses With Central Nervous System Anomalies AJMG Part C: Seminars in Medical Genetics. 2025.

    View article (DOI) PMID: 41449851

  • Hayashi Y, Kajiwara K, Mizuno S, et al. Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders Journal of Human Genetics. 2025.

    View article (DOI) PMID: 41408479

  • Morello W, Armaroli G, Milani D, et al. ReNU Syndrome due to a de novo RNU4-2 Variant as a Novel Genetic Cause of Proteinuria Kidney Medicine. 2025.

    View article (DOI) PMID: 41623289

  • Valenzuela I, Codina-Solà M, Vazquez E, et al. Deep phenotyping of 11 individuals with pathogenic variants in RNU4-2 reveals a clinically recognizable syndrome Genetics in Medicine. 2025.

    View article (DOI) PMID: 41351592

  • Di Letto P, De Leonibus C, Palmieri FP, et al. Reanalysis of Undiagnosed Neurodevelopmental Disorder Cases: From RNU4-2 Variants to Clinical Phenotypes (NEDHAFA) Neurology Genetics. 2025.

    View article (DOI) PMID: 41127311

  • El Chehadeh S, Heide S, Quélin C, et al. Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study Genome Medicine. 2025.

    View article (DOI) PMID: 41044778

  • Leitão E, Santini A, Cogne B, et al. Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies medRxiv (preprint). 2025.

    View article (DOI) PMID: 40950445

  • Greene D, Mendez R, Lees J, et al. Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder medRxiv (preprint). 2025.

    View article (DOI) PMID: 40909831

  • Nakamura K, Kishita Y, Imai-Okazaki A, et al. Identification of a pathogenic RNU4-2 variant in patients with mitochondrial disease: broadening the spectrum of non-coding RNA gene variants in mitochondrial dysfunction Journal of Human Genetics. 2025.

    View article (DOI) PMID: 40696135

  • Kuroda Y, Nagai K, Kawai Y, et al. Genotype-phenotype correlations and phenotypic expansion in a case series of ReNU syndrome associated with RNU4-2 variants (Japan) Journal of Medical Genetics. 2025.

    View article (DOI) PMID: 40413032

  • Bertoli-Avella AM, Ganoza CA, Ferreira M, et al. RNU4-2 monoallelic variants as a leading cause of syndromic neurodevelopmental disorder, including in patients with parental consanguinity Journal of Medical Genetics. 2025.

    View article (DOI) PMID: 40413033

  • Okamoto N, Nishi E, Hasegawa Y, et al. A Clinical Study of Nine Patients With ReNU Syndrome American Journal of Medical Genetics Part A. 2025.

    View article (DOI) PMID: 40546132

  • Jackson A, Thaker N, Blakes A, et al. Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes Nature Genetics. 2025.

    View article (DOI) PMID: 40442284

  • Nava C, Cogne B, Santini A, et al. Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption Nature Genetics. 2025.

    View article (DOI) PMID: 40379786

  • Holling T, von Kroge S, Hecher L, et al. Assessment and treatment of osteoporosis in a patient with a neurodevelopmental disorder caused by a RNU4-2 pathogenic variant (ReNU syndrome) JBMR Plus. 2025.

    View article (DOI) PMID: 40510867

  • Greene D, De Wispelaere K, Lees J, et al. Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy Nature Genetics. 2025.

    View article (DOI) PMID: 40210679

  • De Jonghe J, Kim HC, Adedeji A, et al. Saturation genome editing of RNU4-2 reveals distinct dominant and recessive neurodevelopmental disorders medRxiv (preprint). 2025.

    View article (DOI) PMID: 40297424

  • Bruselles A, Mancini C, Chiriatti L, et al. Expanding the mutational spectrum of ReNU syndrome: insights into 5' stem-loop variants European Journal of Human Genetics. 2025.

    View article (DOI) PMID: 40011755

  • Peñafiel-Sam J, Valenzuela I, Peris P. Severe Osteoporosis in an Adult Subject with RNU4-2 Gene Mutation Calcified Tissue International. 2025.

    View article (DOI) PMID: 39961815

  • Fan S, Yang S, Sun M, et al. Reanalysis of whole genome sequencing ends a diagnostic odyssey of neurodevelopmental disorders caused by RNU4-2 variants Science China Life Sciences. 2025.

    View article (DOI) PMID: 39969744

  • Quinodoz M, Rodenburg K, Cvackova Z, et al. De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa medRxiv (preprint). 2025.

    View article (DOI) PMID: 39830270

2024

  • Barbour K, Friedman J, Bird LM, et al. The Prevalence of RNU4-2-Associated Autosomal Dominant Intellectual Disability Syndrome Pediatric Neurology. 2024.

    View article (DOI) PMID: 39756185

  • Rosenblum J, Beysen D, Jansen AC, et al. RNU4-2-Related Neurodevelopmental Disorder Is Associated With a Recognisable Facial Gestalt Clinical Genetics. 2024.

    View article (DOI) PMID: 39434505

  • Burns VF, Radford EJ. ReNU syndrome - a newly discovered prevalent neurodevelopmental disorder Trends in Genetics. 2024.

    View article (DOI) PMID: 39358183

  • Barbour K, Bainbridge MN, Wigby K, et al. The Face and Features of RNU4-2: A New, Common, Recognizable, Yet Hidden Neurodevelopmental Disorder Pediatric Neurology. 2024.

    View article (DOI) PMID: 39423747

  • Greene D, De Wispelaere K, Lees J, et al. Mutations in the U2 snRNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy medRxiv (preprint). 2024.

    View article (DOI) PMID: 39281759

  • Danovi S. RNU4-2 variants cause neurodevelopmental disorders Nature Genetics (news). 2024.

    View article (DOI) PMID: 39134645

  • Chen Y, Dawes R, Kim HC, et al. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome Nature. 2024.

    View article (DOI) PMID: 38991538

  • Schot R, Ferraro F, Geeven G, et al. Re-analysis of whole genome sequencing ends a diagnostic odyssey: case report of an RNU4-2 related neurodevelopmental disorder Clinical Genetics. 2024.

    View article (DOI) PMID: 38859706

  • Greene D, Thys C, Berry IR, et al. Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders Nature Medicine. 2024.

    View article (DOI) PMID: 38821540

  • Chen Y, Dawes R, Kim HC, et al. RNU4-2 variants in the non-coding spliceosomal snRNA gene are a frequent cause of syndromic neurodevelopmental disorders medRxiv (preprint). 2024.

    View article (DOI) PMID: 38645094

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