Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic...

Non-protein-coding genes are emerging as critical contributors to the etiology of rare diseases, providing key insights into human biology and uncovering novel disease mechanisms. We identified 7 individuals from 4 families with early-onset diabetes (diagnosed aged <5 years) and immune dysregulatory features caused by bi-allelic variants in RNU6ATAC. RNU6ATAC encodes a small nuclear RNA (snRNA) that acts as a catalytic component of the minor spliceosome, a protein-RNA complex that mediates the splicing of ∼700 genes containing U12/minor-type introns. Variant screening of the other 64 minor spliceosome genes in 276 infants with diabetes identified 12 unrelated individuals with bi-allelic disease-causing variants in RNU4ATAC. Bi-allelic pathogenic RNU4ATAC variants are known to cause a variable spectrum of clinical features, which until now did not include diabetes. Clinically, 12/19 RNU6ATAC/RNU4ATAC affected individuals had additional immune dysregulatory features, and 50% of individuals tested were islet-autoantibody positive, strongly supporting an autoimmune etiology for their diabetes. RNA sequencing (RNA-seq) in 3 individuals with bi-allelic RNU6ATAC variants showed a pattern of intron retention in U12-intron-containing genes similar to that seen in RNU4ATAC individuals (n = 3), supporting a shared disease mechanism. Analysis of affected individuals' transcriptomic, methylation, and immune data revealed impaired B cell development and maturation. We conclude that bi-allelic RNU6ATAC variants cause a syndrome of early-onset autoimmune diabetes and immune dysregulation. We further show that infancy-onset diabetes is a feature of RNU4ATAC-opathy. Our work highlights the important role of two snRNAs critical to minor spliceosome function in immune system regulation, providing insights into the pathogenesis of autoimmune diabetes.