A multidisciplinary RNA-guided approach to complement genomic analysis of unsolved patients with an inborn error of immunity - Report - MDSpire

A multidisciplinary RNA-guided approach to complement genomic analysis of unsolved patients with an inborn error of immunity

  • By

  • Willem T. K. Maassen

  • Lotte C. E. T. Pape

  • Tim Niemeijer

  • Anne-Margriet Heijink

  • Martine T. Meems-Veldhuis

  • Daniëlle J. Boerrigter

  • Gerben van der Vries

  • Helga Westers

  • Lennart F. Johansson

  • Kasper J. van der Velde

  • Morris A. Swertz

  • Lude Franke

  • Geertje E. Legger

  • Annechien J. A. Lambeck

  • Abraham Rutgers

  • Iris H. Jonkers

  • Mariëlle E. van Gijn

  • Evelien Zonneveld-Huijssoon

  • May 28, 2026

  • 0 min

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Clinical Report: RNA-Directed Strategy Enhances Diagnosis in IEI Patients

Overview

This study presents a structured RNA-guided approach that improved the diagnostic yield in patients with unresolved inborn errors of immunity (IEI). The method successfully identified conclusive diagnoses in 2 out of 22 patients previously deemed inconclusive by standard genetic testing.

Background

Inborn errors of immunity (IEI) represent a diverse group of over 550 disorders linked to more than 500 genes, with diagnostic rates ranging from 15% to 70%. The complexity of these disorders often leads to missed diagnoses due to variants of uncertain significance and limitations of current genetic testing methods. Enhancing diagnostic accuracy is crucial for timely treatment and management of these patients.

Data Highlights

No numerical data or trial data was provided in the source material.

Key Findings

  • RNA-guided variant interpretation led to a conclusive diagnosis in 2 out of 22 patients with unresolved IEI.
  • A splice variant in IKBKG was identified, explaining the phenotype of one male patient.
  • A pathogenic splice variant in CYBB was detected in a female patient, linked to skewed X-inactivation.
  • A deep-intronic variant in NFKB1 was found, activating a cryptic splice site consistent with NFKB1 haploinsufficiency.
  • Current genetic testing methods yield a diagnostic rate of approximately 38% for IEI.
  • RNA-sequencing can reveal functional effects of genetic variants, potentially increasing diagnostic yield by 4-12%.

Clinical Implications

Integrating RNA-sequencing into routine diagnostics may enhance the identification of causative variants in IEI patients. This approach could lead to more accurate diagnoses and better-targeted treatments.

Conclusion

Revise to reflect only the findings presented in the study without broader implications.

Related Resources & Content

  1. Author(s)/Org, Source, Year -- Title
  2. Genome Medicine, 2025 -- Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort
  3. Journal of Clinical Immunology, 2025 -- Whole Genome Sequencing in 25 Families with Suspected Inborn Errors of Immunity: Diagnostic Yield and Clinical Relevance of Genome-wide Analysis
  4. the pathologist — Unlocking Hidden RNA Signals
  5. Frontiers in Immunology — Enhancing targeted strategies for cancer immunotherapy by elucidating mRNA processing mechanisms
  6. the medicine maker — Immune-Stealth DNA Enables Safer, Large-Scale Genome Writing
  7. Frontiers in Medicine — RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H
  8. Unlocking Hidden RNA Signals
  9. Enhancing targeted strategies for cancer immunotherapy by elucidating mRNA processing mechanisms
  10. Immune-Stealth DNA Enables Safer, Large-Scale Genome Writing
  11. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity | Journal of Human Immunity | Rockefeller University Press
  12. Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort | Genome Medicine | Springer Nature Link
  13. Whole Genome Sequencing in 25 Families with Suspected Inborn Errors of Immunity: Diagnostic Yield and Clinical Relevance of Genome-wide Analysis | Journal of Clinical Immunology | Springer Nature Link

Original Source(s)

A multidisciplinary RNA-guided approach to complement genomic analysis of unsolved patients with an inborn error of immunity

  • by Willem T. K. Maassen, Lotte C. E. T. Pape, Tim Niemeijer, Anne-Margriet Heijink, Martine T. Meems-Veldhuis, Daniëlle J. Boerrigter, Gerben van der Vries, Helga Westers, Lennart F. Johansson, Kasper J. van der Velde, Morris A. Swertz, Lude Franke, Geertje E. Legger, Annechien J. A. Lambeck, Abraham Rutgers, Iris H. Jonkers, Mariëlle E. van Gijn, Evelien Zonneveld-Huijssoon

  • May 28, 2026

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