Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population

Tal Freund, Sarah K. Baxter, Tom Walsh, Hana Golan, Joseph Kapelushnik, Michal Abramsohn-Goldenberg, Shira Benor, Nadav Sarid, Ron Ram, Yifat Alcalay, Reeval Segel, Paul Renbaum, Polina Stepensky, Mary Claire King, Troy R. Torgerson, David Hagin

    Research output: Contribution to journalArticlepeer-review


    Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin’s disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

    Original languageEnglish
    Pages (from-to)151-164
    Number of pages14
    JournalJournal of Clinical Immunology
    Issue number1
    StatePublished - 1 Jan 2023


    • CTL4
    • Georgian Jews
    • IEI
    • Immunedysregulation
    • Inborn errors of immunity
    • LRBA
    • PIDD
    • Primary immunodeficiency disorders

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology


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