Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Paul Tuijnenburg,Scott Hackett,Hana Alachkar,Simon Staines,Sinisa Savic,Ania Manson,Isabella Quinti,Sarita Workman,Lorena Lorenzo,Helen Baxendale,Patrick Yong,Anton T.J Tool,Antony Attwood,Rohit Ghurye,Ilenia Simeoni,Julie Von Ziegenweldt,Ping Yu,Lisa Devlin,Cathal Steele,James Thaventhiran,William Egner,Deborah Whitehorn,Matthias Haimel,Nichola Cooper,Hana Lango Allen,Jesmeen Maimaris,Marie Erwood,Emily Staples,Adrian J Thrasher,Eleanor Dewhurst,Marta Bleda,Alexander B Meijer,Ernest Turro,Naomi Clements-Brod,Dinakantha Kumararatne,Keren Carss,Sofia Grigoriadou,Hayley Clifford,Bobby Gaspar,Abigail Furnell,Salih Tuna,Waseem Qasim,Amy Frary,Siobhan O Burns,Matthew Brown,Debra Fletcher,Fiona Shackley,Nigel Yeatman,Austen Worth,Rosie Hague,Iman Nasir,Richard Antrobus,Shahnaz Bibi,Taco W Kuijpers,Barbara Boardman,Jennifer Martin,Mary Brownlie,Valerie Morrisson,Csaba Halmagyi,Alex Richter,Moira Thomas,Aarnoud Huissoon,Jonathan Stephens,Steve Welch,Fengyuan Hu,Stephen Hughes,William Astle,Claire Booth,Anita Chandra,Elizabeth Mcdermott,Carrock Sewall,Archana Herwadkar,Sadia Noorani,Grant Hayman,Claire Bethune,Lisa Willcocks,Nathalie Kingston,Tim Young,Stephen Jolles,Gururaj Arumugakani,Vera Matser,Sara Lear,Roger James,Michael Browning,Sofie Ashford,Sergey Nejentsev,Chiara Bacchelli,Sarah Goddard,Ariharan Anantharachagan,Tracey Hammerton,Mark Ponsford,Anoop Mistry,Stuart Meacham,Elizabeth Drewe,Paula Rayner-Matthews,Peter Kelleher,Sai Murng,John Dempster,Ravishankar Sargur,Olga Shamardina,Nigel Klein,Machiel H Jansen,Daniel Greene,Rachel Linger,Crina Samarghitean,Suranjith L Seneviratne,Sophie Davies,Hilary Longhurst,Godelieve J De Bree,Hazel Millar,Sofia Papadia,James Laffan,Rutendo Mapeta,Kathleen Stirrups,Marijke Veltman,Daniele Biasci,Zoe Adhya,Catherine Titterton,Pavel Gordins,Lorraine Harper,Julie R Jones ,Ester M M Van Leeuwen ,Willem H Ouwehand ,Christopher J Penkett ,John M Davis ,Karyn Mégy ,Éric Oksenhendler ,Hans J Stauss ,John R Bradley ,F Lucy Raymond ,Stefan Gräf ,Sorena Kiani‐Alikhan ,Tariq El‐Shanawany ,Ellie Quinn ,J D M Edgar ,Kimberly C Gilmour ,Kenneth G C Smith ,Karola Rehnström ,Sri V V Deevi ,Louise C Daugherty ,Rainer Döffinger ,Eduard H T M Ebberink ,Christopher D Watt

doi:10.1016/j.jaci.2018.01.039

Abstract

BackgroundThe genetic cause of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

Highlights

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information
All 16 predicted likely pathogenic variants were private to the PID cohort, and further investigation revealed that all 16 subjects were within the diagnostic criteria of common variable immunodeficiency (CVID) (Table I)
In our study we show that LOF variants in nuclear factor kB subunit 1 (NFKB1) are present in 4% of our cohort of patients with CVID, being the most commonly identified genetic cause of CVID

Summary

Introduction

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. Methods: In the predominantly European study population of principally sporadic unrelated PID cases (n 5 846), a novel Bayesian method identified nuclear factor kB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n 5 390) in the cohort. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Conclusion: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells. (J Allergy Clin Immunol 2018;142:1285-96.)

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