A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome
- 1Big Data Institute, University of Oxford, Oxford, UK
Abstract
ReNU syndrome is a severe neurodevelopmental disorder caused by de novo variants in the spliceosomal small nuclear RNA (snRNA) gene RNU4-2. Pathogenic variants cluster in two distinct structural regions of the U4 snRNA produced by RNU4-2, the T-loop and Stem III. Aberrant 5 splice site selection is a molecular hallmark of ReNU syndrome that correlates with phenotypic severity and could be leveraged as a quantitative biomarker to facilitate preclinical and clinical therapeutic development. We analysed RNA-sequencing data from two independent cohorts totalling 30 individuals with ReNU syndrome and 54 controls. We identified 483 alternative splicing events shared across both cohorts, with the highest concordance in 105 alternative 5 splice-site (A5SS) events. Using these 105 A5SS events, we derived a minimal reproducible signature from only six sites. The splicing signature perfectly distinguished 19 n.64_65insT individuals from 54 controls, and produced no false positives when applied to a further 5,984 whole blood controls. In addition, the signature was specific to variants within the U4-2 T-loop, which are associated with greater clinical severity. Further, we find evidence of alternative splicing events that are specific to variants in Stem III. In a patient-derived induced pluripotent stem cell (iPSC) model of the recurrent RNU4-2 n.64_64insT variant, the splicing signature was fully recapitulated across all stages of differentiation into cortical neuron-like cells. Together, these findings define a robust RNA biomarker for T-loop ReNU syndrome for use in therapeutic development, and illustrate a general framework for portable biomarker discovery in spliceopathies.
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BibTeX
@misc{dawes2026crosstissue,
title = {{A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome}},
author = {R. Dawes and A. Blakes and T. Markati and M. Griffiths and B. Cogne and T. S. Barakat and J. C. Barrett and C. Rinaldi and S. J. Sanders and N. Whiffin},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.26364077},
url = {https://www.medrxiv.org/content/10.64898/2026.09.26.26364077v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - A cross-tissue splicing signature as a quantitative biomarker for ReNU syndrome
AU - R. Dawes
AU - A. Blakes
AU - T. Markati
AU - M. Griffiths
AU - B. Cogne
AU - T. S. Barakat
AU - J. C. Barrett
AU - C. Rinaldi
AU - S. J. Sanders
AU - N. Whiffin
PY - 2026
DA - 2026/09/26
PB - medRxiv
DO - 10.64898/2026.09.26.26364077
UR - https://www.medrxiv.org/content/10.64898/2026.09.26.26364077v2
AB - ReNU syndrome is a severe neurodevelopmental disorder caused by de novo variants in the spliceosomal small nuclear RNA (snRNA) gene RNU4-2. Pathogenic variants cluster in two distinct structural regions of the U4 snRNA produced by RNU4-2, the T-loop and Stem III. Aberrant 5 splice site selection is a molecular hallmark of ReNU syndrome that correlates with phenotypic severity and could be leveraged as a quantitative biomarker to facilitate preclinical and clinical therapeutic development. We analysed RNA-sequencing data from two independent cohorts totalling 30 individuals with ReNU syndrome and 54 controls. We identified 483 alternative splicing events shared across both cohorts, with the highest concordance in 105 alternative 5 splice-site (A5SS) events. Using these 105 A5SS events, we derived a minimal reproducible signature from only six sites. The splicing signature perfectly distinguished 19 n.64_65insT individuals from 54 controls, and produced no false positives when applied to a further 5,984 whole blood controls. In addition, the signature was specific to variants within the U4-2 T-loop, which are associated with greater clinical severity. Further, we find evidence of alternative splicing events that are specific to variants in Stem III. In a patient-derived induced pluripotent stem cell (iPSC) model of the recurrent RNU4-2 n.64_64insT variant, the splicing signature was fully recapitulated across all stages of differentiation into cortical neuron-like cells. Together, these findings define a robust RNA biomarker for T-loop ReNU syndrome for use in therapeutic development, and illustrate a general framework for portable biomarker discovery in spliceopathies.
ER -