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Peer-reviewedCC BYJournal of human immunity

Genotype-phenotype analysis in 333 individuals with heterozygous variants in NFKB1.

  • Sophia Marie Armbruster1,2
  • Andres Caballero-Oteyza2,3
  • Oliver Bartsch4
  • Tiziana Lorenzini5
  • Hassan Abolhassani6
  • Samantha Chan7
  • Luis Ignacio González Granado8
  • Victor Garcia-Bustos9,10
  • Marta Dafne Cabañero Navalon9,11
  • Nazanin Fathi12
  • Nima Rezaei12
  • Mathieu Fusaro13,14
4 more authors
  • Roger Colobran15
  • Kaan Boztug16,17,18,19
  • Michele Proietti2,3
  • Bodo Grimbacher1,2,20,21,3
21 affiliations
  1. 1Faculty of Medicine, Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  2. 2Faculty of Medicine, Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  3. 3RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg , Freiburg, Germany.
  4. 4Department of Human Genetics, Medical Care Center, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  5. 5Division of Immunology and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.
  6. 6Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  7. 7Department of Clinical Immunology & Allergy, Royal Melbourne Hospital, Melbourne, Australia.
  8. 8Primary Immunodeficiencies Unit, Department of Pediatrics, Hospital 12 Octubre, Research Institute University Hospital 12 de Octubre Complutense School of Medicine, Madrid, Spain.
  9. 9Primary Immunodeficiencies Unit, Department of Internal Medicine, University and Polytechnic Hospital La Fe, Valencia, Spain.
  10. 10Severe Infection Research Group, Health Research Institute La Fe , Valencia, Spain.
  11. 11Research Group of Chronic Diseases and HIV Infection, Health Research Institute La Fe , Valencia, Spain.
  12. 12Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences , Tehran, Iran.
  13. 13Immunology Department Laboratory, Referral Medical Biology Laboratory, Toulouse University Hospital Center, Toulouse, France.
  14. 14INFINITY - Toulouse Institute for Infectious and Inflammatory Diseases, INSERM, U1291, CNRS U5051, University Toulouse III , Toulouse, France.
  15. 15Translational Immunology Research Group, Immunology Division, Department of Cell Biology, Physiology and Immunology, Vall D'Hebron Research Institute, Vall D'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.
  16. 16Clinic for Pediatric Immunology and Rheumatology, University of Bonn, University Hospital Bonn , Bonn, Germany.
  17. 17St. Anna Children's Cancer Research Institute , Vienna, Austria.
  18. 18Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
  19. 19CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences , Vienna, Austria.
  20. 20German Center for Infection Research, Satellite Center Freiburg , Freiburg, Germany.
  21. 21Centre for Integrative Biological Signaling Studies, Albert-Ludwigs University , Freiburg, Germany.
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Abstract

Heterozygous germline variants in NFKB1 can be classified into variants with "known protein defect" and "unknown protein effect." However, beyond this, NFKB1 variants may be additionally categorized into at least eight distinct variant classes. We conducted a literature review of 67 papers reporting on NFKB1 variants and included four additional individuals, carrying previously unreported NFKB1 variants. We identified 333 individuals with unique variants in NFKB1. Our compiled data revealed that there is no sex predilection, the penetrance-including all heterozygous carriers-was 78%, and the mean age of onset for the "known protein defect cohort" was 21.2 years. Individuals harboring variants with a known protein defect demonstrated a higher frequency of malignancies and autoimmune disorders. However, these individuals were less frequently classified as affected than individuals with variants with unknown protein defect. Carriers of whole NFKB1 gene deletions had a significantly higher penetrance to being designated as "affected," but beyond this, the clinical manifestations did not differ between variant classes.

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Cite

BibTeXRIS
BibTeX
@article{armbruster2026genotypephenotype,
  title = {{Genotype-phenotype analysis in 333 individuals with heterozygous variants in NFKB1.}},
  author = {Sophia Marie Armbruster and Andres Caballero-Oteyza and Oliver Bartsch and Tiziana Lorenzini and Hassan Abolhassani and Samantha Chan and Luis Ignacio González Granado and Victor Garcia-Bustos and Marta Dafne Cabañero Navalon and Nazanin Fathi and Nima Rezaei and Mathieu Fusaro and Roger Colobran and Kaan Boztug and Michele Proietti and Bodo Grimbacher},
  journal = {Journal of human immunity},
  year = {2026},
  month = oct,
  doi = {10.70962/jhi.20260076},
  url = {https://europepmc.org/article/MED/42895832},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Genotype-phenotype analysis in 333 individuals with heterozygous variants in NFKB1.
AU  - Sophia Marie Armbruster
AU  - Andres Caballero-Oteyza
AU  - Oliver Bartsch
AU  - Tiziana Lorenzini
AU  - Hassan Abolhassani
AU  - Samantha Chan
AU  - Luis Ignacio González Granado
AU  - Victor Garcia-Bustos
AU  - Marta Dafne Cabañero Navalon
AU  - Nazanin Fathi
AU  - Nima Rezaei
AU  - Mathieu Fusaro
AU  - Roger Colobran
AU  - Kaan Boztug
AU  - Michele Proietti
AU  - Bodo Grimbacher
PY  - 2026
DA  - 2026/10/19
JO  - Journal of human immunity
DO  - 10.70962/jhi.20260076
UR  - https://europepmc.org/article/MED/42895832
AB  - Heterozygous germline variants in NFKB1 can be classified into variants with "known protein defect" and "unknown protein effect." However, beyond this, NFKB1 variants may be additionally categorized into at least eight distinct variant classes. We conducted a literature review of 67 papers reporting on NFKB1 variants and included four additional individuals, carrying previously unreported NFKB1 variants. We identified 333 individuals with unique variants in NFKB1. Our compiled data revealed that there is no sex predilection, the penetrance-including all heterozygous carriers-was 78%, and the mean age of onset for the "known protein defect cohort" was 21.2 years. Individuals harboring variants with a known protein defect demonstrated a higher frequency of malignancies and autoimmune disorders. However, these individuals were less frequently classified as affected than individuals with variants with unknown protein defect. Carriers of whole NFKB1 gene deletions had a significantly higher penetrance to being designated as "affected," but beyond this, the clinical manifestations did not differ between variant classes.
SN  - 3065-8993
ER  -