Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients.
[BACKGROUND] Homozygous or compound heterozygous variants in , which transcribes a non-coding RNA component of the minor spliceosome, have been associated with a spectrum of disorders, collectively kn
APA
Lovric S, Berking AC, et al. (2026). Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients.. Orphanet journal of rare diseases, 21(1). https://doi.org/10.1186/s13023-026-04300-x
MLA
Lovric S, et al.. "Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients.." Orphanet journal of rare diseases, vol. 21, no. 1, 2026.
PMID
41808109
Abstract
[BACKGROUND] Homozygous or compound heterozygous variants in , which transcribes a non-coding RNA component of the minor spliceosome, have been associated with a spectrum of disorders, collectively known as -related spliceosomeopathies. The phenotypic spectrum of -related disease is characterized by dysmorphic features, growth delay, neurological and skeletal features, whose severity ranges from the microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) to the milder Roifman syndrome.
[OBJECTIVES] To characterize the clinical spectrum and evaluate long-term outcomes of -related diseases.
[METHODS] We evaluated the phenotypic features of four novel patients with deleterious variants, diagnosed by means of whole genome sequencing. Same features were evaluated in previously published cases, identified by literature research on PubMed.
[RESULTS] We identified four novel cases with deleterious compound heterozygous variants in , which were not restricted to the 5’ stem-loop, including three adult patients. Reported cases expand the clinical spectrum of -related disorders, highlighting renal disease, autoimmunity and systemic inflammation as possibly more frequent yet previously under-recognized features. Immunological investigations reveal enhanced HLA-DR and PD-1 expression in T cells from tested patients, suggesting T cell activation and exhaustion. Reevaluation of all previously published cases confirms the strong correlation of variants located exclusively at the 5’ stem-loop with severe lethal disease falling under MOPD1. Genotypes carrying at least one variant that spares the 5′ stem-loop are associated with a milder phenotype and later onset.
[CONCLUSION] Homozygous or compound heterozygous variants affecting the 5’ stem-loop region are associated with severe phenotypes and adverse disease courses. In contrast, genotypes sparing the critical 5′ stem-loop region of can cause a complex phenotype that is not necessarily dominated by dysmorphic features or growth failure, but rather by immunodeficiency and immune dysregulation.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13023-026-04300-x.
[OBJECTIVES] To characterize the clinical spectrum and evaluate long-term outcomes of -related diseases.
[METHODS] We evaluated the phenotypic features of four novel patients with deleterious variants, diagnosed by means of whole genome sequencing. Same features were evaluated in previously published cases, identified by literature research on PubMed.
[RESULTS] We identified four novel cases with deleterious compound heterozygous variants in , which were not restricted to the 5’ stem-loop, including three adult patients. Reported cases expand the clinical spectrum of -related disorders, highlighting renal disease, autoimmunity and systemic inflammation as possibly more frequent yet previously under-recognized features. Immunological investigations reveal enhanced HLA-DR and PD-1 expression in T cells from tested patients, suggesting T cell activation and exhaustion. Reevaluation of all previously published cases confirms the strong correlation of variants located exclusively at the 5’ stem-loop with severe lethal disease falling under MOPD1. Genotypes carrying at least one variant that spares the 5′ stem-loop are associated with a milder phenotype and later onset.
[CONCLUSION] Homozygous or compound heterozygous variants affecting the 5’ stem-loop region are associated with severe phenotypes and adverse disease courses. In contrast, genotypes sparing the critical 5′ stem-loop region of can cause a complex phenotype that is not necessarily dominated by dysmorphic features or growth failure, but rather by immunodeficiency and immune dysregulation.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13023-026-04300-x.