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

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

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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.

Original language	English
Article number	109181
Number of pages	5
Journal	CLINICAL IMMUNOLOGY
Volume	246
Early online date	2022
DOIs	https://doi.org/10.1016/j.clim.2022.109181
Publication status	Published - Jan 2023
Publication type	A1 Journal article-refereed

Funding

Funding was received by Emil Aaltonen Foundation (ET), Biomedicum Foundation (ET), The Finnish Medical Foundation (ET), Sanofi-Genzyme (JSa), Academy of Finland (MV), Sigrid Jusélius Foundation (JK), Oulu University Hospital VTR (TH), The Foundation for Pediatric Research (MS), HUS Pediatric Research Center and Helsinki University Hospital Research Funds (MS, KKE), Finska Läkaresällskapet (KKE) and the Erkko Foundation (KKE, MS).

Keywords

Autoinflammation
Common variable immunodeficiency
Hypogammaglobulinemia
Inborn errors of immunity
NFKB1

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1016/j.clim.2022.109181Licence: CC BY

1-s2.0-S1521661622002625-mainFinal published version, 477 KBLicence: CC BY

https://urn.fi/URN:NBN:fi:tuni-202302011963Licence: CC BY

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Tuovinen, E. A., Kuismin, O., Soikkonen, L., Martelius, T., Kaustio, M., Hämäläinen, S., Viskari, H., Syrjänen, J., Wartiovaara-Kautto, U., Eklund, K. K., Saarela, J., Varjosalo, M., Kere, J., Hautala, T., & Seppänen, M. R. J. (2023). Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae. CLINICAL IMMUNOLOGY, 246, Article 109181. https://doi.org/10.1016/j.clim.2022.109181

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

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",

author = "Tuovinen, {Elina A.} and Outi Kuismin and Leila Soikkonen and Timi Martelius and Meri Kaustio and Sari H{\"a}m{\"a}l{\"a}inen and Hanna Viskari and Jaana Syrj{\"a}nen and Ulla Wartiovaara-Kautto and Eklund, {Kari K.} and Janna Saarela and Markku Varjosalo and Juha Kere and Timo Hautala and Sepp{\"a}nen, {Mikko R.J.}",

note = "Funding Information: Funding was received by Emil Aaltonen Foundation (ET), Biomedicum Foundation (ET), The Finnish Medical Foundation (ET), Sanofi-Genzyme (JSa), Academy of Finland (MV), Sigrid Jus{\'e}lius Foundation (JK), Oulu University Hospital VTR (TH), The Foundation for Pediatric Research (MS), HUS Pediatric Research Center and Helsinki University Hospital Research Funds (MS, KKE), Finska L{\"a}kares{\"a}llskapet (KKE) and the Erkko Foundation (KKE, MS). Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = jan,

doi = "10.1016/j.clim.2022.109181",

language = "English",

volume = "246",

journal = "CLINICAL IMMUNOLOGY",

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Tuovinen, EA, Kuismin, O, Soikkonen, L, Martelius, T, Kaustio, M, Hämäläinen, S, Viskari, H , Syrjänen, J, Wartiovaara-Kautto, U, Eklund, KK, Saarela, J, Varjosalo, M, Kere, J, Hautala, T & Seppänen, MRJ 2023, 'Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae', CLINICAL IMMUNOLOGY, vol. 246, 109181. https://doi.org/10.1016/j.clim.2022.109181

TY - JOUR

T1 - Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae

AU - Tuovinen, Elina A.

AU - Kuismin, Outi

AU - Soikkonen, Leila

AU - Martelius, Timi

AU - Kaustio, Meri

AU - Hämäläinen, Sari

AU - Viskari, Hanna

AU - Syrjänen, Jaana

AU - Wartiovaara-Kautto, Ulla

AU - Eklund, Kari K.

AU - Saarela, Janna

AU - Varjosalo, Markku

AU - Kere, Juha

AU - Hautala, Timo

AU - Seppänen, Mikko R.J.

N1 - Funding Information: Funding was received by Emil Aaltonen Foundation (ET), Biomedicum Foundation (ET), The Finnish Medical Foundation (ET), Sanofi-Genzyme (JSa), Academy of Finland (MV), Sigrid Jusélius Foundation (JK), Oulu University Hospital VTR (TH), The Foundation for Pediatric Research (MS), HUS Pediatric Research Center and Helsinki University Hospital Research Funds (MS, KKE), Finska Läkaresällskapet (KKE) and the Erkko Foundation (KKE, MS). Publisher Copyright: © 2022 The Authors

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

KW - Autoinflammation

KW - Common variable immunodeficiency

KW - Hypogammaglobulinemia

KW - Inborn errors of immunity

KW - NFKB1

U2 - 10.1016/j.clim.2022.109181

DO - 10.1016/j.clim.2022.109181

M3 - Article

C2 - 36356849

AN - SCOPUS:85142516864

SN - 1521-6616

VL - 246

JO - CLINICAL IMMUNOLOGY

JF - CLINICAL IMMUNOLOGY

M1 - 109181

ER -

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

Abstract

Funding

Keywords

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ASJC Scopus subject areas

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