Clinical and immunological variability in RNU4ATAC-associated disorders: a case report and review of immunological features

Vollständiger Abstract

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Background: RNU4ATAC encodes a critical component of the minor spliceosome, and biallelic variants are associated with a spectrum of syndromic disorders, including Roifman syndrome, microcephalic osteodysplastic primordial dwarfism type I, and Lowry–Wood syndrome. These conditions demonstrate marked clinical and immunological heterogeneity, with overlapping yet variably expressed features. Aim: To describe the clinical and immunological phenotype of a patient with an RNU4ATAC pathogenic variant and to expand the current understanding of disease variability within RNU4ATAC-associated disorders. Methods: We report a detailed clinical, genetic, and immunological evaluation of a 15-year-old male with multisystem involvement. Whole-genome sequencing was performed to identify the underlying genetic defect. Immunological assessment included lymphocyte subset analysis and evaluation of immunoglobulin levels and specific antibody responses. A review of previously reported cases was conducted to contextualize the findings. Results: The patient, born to consanguineous parents, presented with developmental delay, pancytopenia, endocrinopathies (hypothyroidism and type 1 diabetes mellitus), and renal involvement (mesangioproliferative glomerulonephritis). Genetic analysis revealed a homozygous non-coding pathogenic variant (n.53C>T) in RNU4ATAC. Immunological evaluation demonstrated T-cell lymphopenia with a reversed naïve-to-memory ratio, while immunoglobulin levels and specific antibody responses were preserved. Notably, the patient lacked skeletal dysplasia, a commonly reported feature of RNU4ATAC-associated syndromes. Hematopoietic stem cell transplantation was considered but deferred due to advanced liver disease. Conclusion: This case highlights a non-classical presentation of RNU4ATAC-associated disease with prominent multisystem involvement and isolated T-cell immunodeficiency in the absence of skeletal abnormalities. These findings emphasize the importance of comprehensive immunological evaluation regardless of presenting features. Statement of novelty: To our knowledge, this is the first report of the homozygous RNU4ATAC n.53C>T variant presenting with a non-classical multisystem phenotype, isolated T-cell immunodeficiency, and absence of skeletal dysplasia, together with a review of previously reported cases with available immunological data.