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Background <p>Homozygous or compound heterozygous variants in <i>RNU4ATAC</i>, which transcribes a non-coding RNA component of the minor spliceosome, have been associated with a spectrum of disorders, collectively known as <i>RNU4ATAC</i>-related spliceosomeopathies. The phenotypic spectrum of <i>RNU4ATAC</i>-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.</p> Objectives <p>To characterize the clinical spectrum and evaluate long-term outcomes of <i>RNU4ATAC</i>-related diseases.</p> Methods <p>We evaluated the phenotypic features of four novel patients with deleterious <i>RNU4ATAC</i> variants, diagnosed by means of whole genome sequencing. Same features were evaluated in previously published cases, identified by literature research on PubMed.</p> Results <p>We identified four novel cases with deleterious compound heterozygous variants in <i>RNU4ATAC</i>, which were not restricted to the 5’ stem-loop, including three adult patients. Reported cases expand the clinical spectrum of <i>RNU4ATAC</i>-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 <i>RNU4ATAC</i> 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.</p> Conclusion <p>Homozygous or compound heterozygous <i>RNU4ATAC</i> 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 <i>RNU4ATAC</i> can cause a complex phenotype that is not necessarily dominated by dysmorphic features or growth failure, but rather by immunodeficiency and immune dysregulation.</p>

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Phenotypic spectrum of RNU4ATAC-related spliceosomopathies: four novel cases and integrated reevaluation of previously reported patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Svjetlana Lovric,
  • Ann-Cathrine Berking,
  • Felix C. Ringshausen,
  • Julia Körholz,
  • Joseph Porrmann,
  • Sylvia Hütter,
  • Jan H. Bräsen,
  • Nataliya di Donato,
  • Kai M. Schmidt-Ott,
  • Torsten Witte,
  • Sandra von Hardenberg,
  • Georgios Sogkas

摘要

Background

Homozygous or compound heterozygous variants in RNU4ATAC, which transcribes a non-coding RNA component of the minor spliceosome, have been associated with a spectrum of disorders, collectively known as RNU4ATAC-related spliceosomeopathies. The phenotypic spectrum of RNU4ATAC-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 RNU4ATAC-related diseases.

Methods

We evaluated the phenotypic features of four novel patients with deleterious RNU4ATAC 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 RNU4ATAC, which were not restricted to the 5’ stem-loop, including three adult patients. Reported cases expand the clinical spectrum of RNU4ATAC-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 RNU4ATAC 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 RNU4ATAC 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 RNU4ATAC can cause a complex phenotype that is not necessarily dominated by dysmorphic features or growth failure, but rather by immunodeficiency and immune dysregulation.