322: Bi-allelic RNU6ATAC and RNU4ATAC variants cause infancy-onset autoimmune diabetes via minor spliceosome U12 intron retention

Johnson MB et al., The American Journal of Human Genetics - Bi-allelic variants in snRNAs RNU6ATAC and RNU4ATAC cause infancy-onset autoimmune diabetes in humans, with RNA-seq showing U12 intron retention and impaired B cell development. Key terms: RNU6ATAC, RNU4ATAC, minor spliceosome, U12 intron retention, autoimmune diabetes. Study Highlights:In human infants with early-onset diabetes and immune dysregulation, the authors used genome sequencing, RNA-seq, DNA methylation deconvolution, WGCNA, Sanger sequencing, and flow cytometry to define a genetic syndrome. They identified 19 individuals with bi-allelic RNU6ATAC or RNU4ATAC variants and RNA-seq revealed significant U12 intron retention in 274 genes, 94% of which are known U12-intron-containing genes. Multi-omic analyses and targeted immune profiling showed reduced naive B cells and abnormal B cell maturation. Half of tested individuals were GADA-positive, supporting an autoimmune mechanism for the diabetes in these snRNA spliceosome disorders. Conclusion:Bi-allelic pathogenic variants in RNU6ATAC cause early-onset autoimmune diabetes with immune dysregulation and bi-allelic RNU4ATAC variants extend RNU4ATAC-opathy to include infancy-onset autoimmune diabetes. Music:Enjoy the music based on this article at the end of the episode. Article title:Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes First author:Johnson MB Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.02.017 Reference:Johnson MB, Russ-Silsby J, Blair PA, Govier M, Bonfield G, Domingo-Vila C, EXE-T1D consortium, ATAC clinical consortium, Wakeling MN, Oram RA, Flanagan SE, Tree TIM, Patel KA, Hattersley AT, De Franco E. Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes. The American Journal of Human Genetics. 2026 Apr 2;113:1–11. https://doi.org/10.1016/j.ajhg.2026.02.017 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/rnu6atac-rnu4atac-minor-spliceosome QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-03-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript portions describing (a) minor spliceosome biology and snRNA function, (b) genetic findings in RNU6ATAC and RNU4ATAC, (c) U12 intron retention as a shared mechanism, (d) B cell development impairment and multi-omic immune profiling, (e) autoimmunity evidence (GADA positivity), (f) clinical phenoty- transcript topics: Minor spliceosome biology and U12 introns; RNU6ATAC bi-allelic variants; RNU4ATAC bi-allelic variants and interaction with RNU6ATAC; RNA-seq intron retention in U12 genes; B cell development and maturation defects; Islet autoantibody positivity in early-onset diabetes QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- 19... Chapters (00:00:11) - The dark matter of human genetics(00:06:06) - Common mutations in the RNU4ATAK gene cause diabetes(00:12:50) - The genetics of autoimmune diabetes