Abstract
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.
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We would like to thank our patients and their families for their support and collaboration. In addition, we thank Prof. Ephrat Levy-Lahad (Director of the Medical Genetics Institute at the Shaare Zedek Medical Center, Jerusalem, Israel) for sharing DNA samples of Georgian Jewish donors.
Funding
D.H. is funded by the Alrov Foundation and the Joint Tel-Aviv Sourasky Medical Center and The Weizmann Institute of Science Research Grant. S.K.B., T.W., and M.C.K. were funded by National Institutes of Health grant R35 CA197458.
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TF, SB, and DH: study conception and design, acquisition of data, analysis and interpretation of data, and manuscript preparation. TW, YA, RS, and PR: acquisition of data, analysis and interpretation of data, and manuscript preparation. HG, JK, MAG, SB, NS, and RR: provided critical clinical care and data. MCK and TRT: analysis and interpretation of data and manuscript preparation.
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Freund, T., Baxter, S.K., Walsh, T. et al. Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population. J Clin Immunol 43, 151–164 (2023). https://doi.org/10.1007/s10875-022-01358-7
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DOI: https://doi.org/10.1007/s10875-022-01358-7