Evidence map›Paper›PMID 41808409›Full record

ArticleHGG advances2026

Bi-allelic RNU6ATAC variants cause a minor spliceopathy characterized by transcriptome-wide minor intron retention and multisystem manifestations.

Rodrigo Mendez, Taylor M Arriaga, Jialan Ma, Devon E Bonner, Sara Emami, Rebecca J Levy, Afaf Alsagheir, Bader Alhaddad, Khadijah Bakur, Rachel A Ungar and 18 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in HGG advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Rodrigo MendezDivision of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. Electronic address: mendezh@stanford.edu.
Taylor M ArriagaDepartment of Genetics, Stanford University, Stanford, CA, USA.
Jialan MaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Devon E BonnerDivision of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Sara EmamiDepartment of Genetics, Stanford University, Stanford, CA, USA.
Rebecca J LevyDivision of Child Neurology, Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Afaf AlsagheirDepartment of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Bader AlhaddadLifera Omics, Riyadh, Saudi Arabia.
Khadijah BakurLifera Omics, Riyadh, Saudi Arabia.
Rachel A UngarDepartment of Genetics, Stanford University, Stanford, CA, USA; Stanford Center for Biomedical Ethics, Stanford University, Stanford, CA, USA.
Dena R MatalonDivision of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Alexander M MillerDepartment of Pathology, Stanford University, Stanford, CA, USA.
Jonathan NguyenDepartment of Pathology, Stanford University, Stanford, CA, USA.
Kevin S SmithDepartment of Pathology, Stanford University, Stanford, CA, USA.
Stuart A ScottDepartment of Pathology, Stanford University, Stanford, CA, USA; Clinical Genomics Laboratory, Stanford Medicine, Stanford, CA, USA.
Linda LiaoClinical Genomics Laboratory, Stanford Medicine, Stanford, CA, USA.
Zena NgClinical Genomics Laboratory, Stanford Medicine, Stanford, CA, USA.
Shruti MarwahaDivision of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
Alistair WardDepartment of Human Genetics, University of Utah, Salt Lake City, UT, USA; Frameshift Labs, Cambridge, MA, USA.
Undiagnosed Diseases Network
Genomics Research to Elucidate the Genetics of Rare Diseases Consortium
Danica NovacicUndiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Fowzan S AlkurayaCollege of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Lifera Omics, Riyadh, Saudi Arabia; Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Jonathan A BernsteinDivision of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Vijay S GaneshProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Anne O'Donnell-LuriaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Stephen B MontgomeryDepartment of Genetics, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA.
Matthew T WheelerDivision of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA. Electronic address: wheelerm@stanford.edu.

Funding

Stanford Mendelian Genomics Research CenterU01HG011762 · NHGRI · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, Stephen Montgomery · 2021 to 2026
$16.7M
Center for Undiagnosed Diseases at StanfordU01NS134358 · NINDS · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, HOLLY K TABOR · 2023 to 2026
$3.1M
Determining How CACNA1C Variants Cause Interneuron PathophysiologyK08NS136775 · NINDS · STANFORD UNIVERSITY · PI REBECCA Jeannette LEVY · 2025 to 2026
$447k
NHGRI NIH HHS U01 HG011762NINDS NIH HHS K08 NS136775NINDS NIH HHS U01 NS134358
6 · The paper itself

Abstract

We report three individuals with bi-allelic variants in RNU6ATAC, which encodes the U6atac minor spliceosomal small nuclear RNA (snRNA), causing a multisystem minor spliceopathy. Through RNA sequencing analysis, we identified a distinctive excess of minor intron retention (MIR) in two unrelated individuals, which guided the identification of bi-allelic RNU6ATAC variants. The discovery cohort presented with variable multisystem manifestations. One individual presented with refractory epilepsy, microcephaly, developmental delay, ataxia, bilateral toe syndactyly, hypereosinophilia, and short stature, whereas the other exhibited failure to thrive, short stature, primary hypothyroidism, combined variable immunodeficiency, eosinophilic colitis, ichthyosis vulgaris, scoliosis, and chronic inflammatory demyelinating polyneuropathy without neurodevelopmental involvement. Despite organ-specific variation, both individuals displayed impaired growth and eosinophil-driven inflammation. Recently, we identified a third affected individual from an independent cohort whose phenotype bridges these features, combining microcephaly, growth failure with severe immunodeficiency, and skeletal abnormalities. The distinctive excess of MIR outliers in the discovery cohort supports minor spliceosome dysfunction, mirroring the molecular signature of RNU4ATAC-opathy. These findings nominate RNU6ATAC as a disease-associated gene, defining an expanded clinical spectrum of minor spliceopathies. Our study supports the power of integrating genomic and transcriptomic approaches for diagnosing splicing disorders and highlights the critical role of spliceosomal snRNAs in human disease.

Indexed as

AllelesIntronsRNA, Small NuclearRNA SplicingTranscriptomeChildChild, PreschoolFemaleHumansMalePhenotypeRNA, Small NuclearRNU4ATAC RNA, humanbioinformaticsminor intron-containing genesminor intron retentionminor spliceosomeRNU4ATACRNU6ATACtranscriptome-wide

Identifiers

PMID41808409
PMCPMC13049632

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.