Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Elina A Tuovinen; Outi Kuismin; Leila Soikkonen; Timi Martelius; Meri Kaustio; Sari Hämäläinen; Hanna Viskari; Jaana Syrjänen; Ulla Wartiovaara-Kautto; Kari K Eklund; Janna Saarela; Markku Varjosalo; Juha Kere; Timo Hautala; Mikko R J Seppänen

doi:10.1016/j.clim.2022.109181

Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

Clin Immunol. 2023 Jan:246:109181. doi: 10.1016/j.clim.2022.109181. Epub 2022 Nov 8.

Authors

Affiliations

¹ Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
² PEDEGO Research Unit, University of Oulu, Oulu, Finland; Department of Clinical Genetics and Medical Research Center, Oulu University Hospital, Oulu, Finland.
³ Inflammation Center, Department of Infectious Disease, Helsinki University Hospital, Helsinki, Finland.
⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁵ Department of Medicine, Institute of Clinical Medicine/ Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
⁶ Department of Internal Medicine, Tampere University Hospital, Tampere, Finland; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁷ Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁸ Department of Rheumatology, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Orton Orthopedic Hospital, Helsinki, Finland.
⁹ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
¹⁰ Systems Biology Research Group and Proteomics Unit, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
¹¹ Folkhälsan Research Center, Helsinki, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland.
¹² Research Unit of Biomedicine, University of Oulu, Oulu, Finland; Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
¹³ Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center and Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland. Electronic address: mikko.seppanen@hus.fi.

PMID: 36356849
DOI: 10.1016/j.clim.2022.109181

Abstract

Nuclear factor κ light-chain enhancer of activated B cells (NF-κB) family of evolutionarily conserved transcription factors are involved in key cellular signaling pathways. Previously, hypogammaglobulinemia and common variable immunodeficiency (CVID)-like phenotypes have been associated with NFKB1 variants and loss-of-function NFKB1 variants have been reported as the most common monogenic cause for CVID among Europeans. Here, we describe a Finnish cohort of NFKB1 carriers consisting of 31 living subjects in six different families carrying five distinct heterozygous variants. In contrast to previous reports, the clinical penetrance was not complete even with advancing age and the prevalence of CVID/hypogammaglobulinemia was significantly lower, whereas (auto)inflammatory manifestations were more common (42% of the total cohort). At current stage of knowledge, routine genetic screening of asymptomatic individuals is not recommended, but counseling of potential adult carriers seems necessary.

Keywords: Autoinflammation; Common variable immunodeficiency; Hypogammaglobulinemia; Inborn errors of immunity; NFKB1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinemia
Common Variable Immunodeficiency* / genetics
Follow-Up Studies
Humans
Immunologic Deficiency Syndromes* / genetics
NF-kappa B p50 Subunit / genetics
NF-kappa B* / genetics

Substances

NF-kappa B
NF-kappa B p50 Subunit
NFKB1 protein, human