318: RNU6ATAC variants cause U6atac-driven minor spliceopathy with transcriptome-wide minor intron retention

Mendez R et al., Human Genetics and Genomics Advances, Journal Pre-proof - Biallelic RNU6ATAC variants disrupt the U6atac minor spliceosomal snRNA, causing transcriptome-wide minor intron retention and short stature with variable multisystem manifestations. Key terms: RNU6ATAC, U6atac, minor spliceosome, minor intron retention, whole-genome sequencing.

Study Highlights:
This study analyzed three unrelated human individuals using RNA-seq on whole-blood and fibroblasts and applied a FRASER-based minor intron retention (MIR) outlier pipeline alongside whole-genome sequencing. The integrated approach identified biallelic RNU6ATAC variants that map to U4atac–U6atac Stem I/II and the central stem-loop of U6atac. Affected individuals show transcriptome-wide excess MIR (for example A1 exhibited 254 MIR outliers in whole blood and B1 exhibited 16 MIR outliers in fibroblasts), indicating impaired minor spliceosome function. The molecular defect correlates with impaired growth and variable multisystem phenotypes including immunodeficiency and neurodevelopmental involvement.

Conclusion:
Biallelic RNU6ATAC variants cause a multisystem minor spliceopathy defined by transcriptome-wide minor intron retention and variable short stature, immunologic, and neurodevelopmental manifestations.

Music:
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Article title:
Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations

First author:
Mendez R

Journal:
Human Genetics and Genomics Advances, Journal Pre-proof

DOI:
10.1016/j.xhgg.2026.100588

Reference:
Mendez R, Arriaga TM, Ma J, Bonner DE, Emami S, Levy RJ, Alsagheir A, Alhaddad B, Bakur K, Ungar RA, Matalon DR, Miller AM, Nguyen J, Smith KS, Scott SA, Liao L, Ng Z, Marwaha S, Ward A, Undiagnosed Diseases Network, Genomics Research to Elucidate the Genetics of Rare Diseases Consortium, Novacic D, Alkuraya FS, Bernstein JA, Ganesh VS, O’Donnell-Luria A, Montgomery SB, Wheeler MT, Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations, Human Genetics and Genomics Advances (2026), doi: https://doi.org/10.1016/j.xhgg.2026.100588

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing MIR as a transcriptome-wide effect, structural disruption of U4atac–U6atac, FRASER MIR filtering, need for WGS over WES, CADD/conservation evidence, tissue-specific effects, and the bridging C1 phenotype.
- transcript topics: Minor intron retention (MIR) and transcriptome-wide MIR pattern; RNU6ATAC structural disruption (Stem I/II and central stem-loop); FRASER MIR outlier analysis and tissue specificity; Whole-genome sequencing vs whole-exome sequencing; CADD scores and evolutionary conservation; Clinical bridging phenotype (A1, B1, C1) and spectrum of RNU6ATAC-opathy

QC Summary:
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