{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T03:28:28Z","timestamp":1778210908361,"version":"3.51.4"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in <jats:italic>RAB27A<\/jats:italic>, <jats:italic>FBP1 (<\/jats:italic>Fructose-1,6-bisphosphatase 1<jats:italic>)<\/jats:italic> and <jats:italic>ACAD9 (<\/jats:italic>Acyl-CoA dehydrogenase family member 9<jats:italic>).<\/jats:italic> Variants in <jats:italic>RAB27A<\/jats:italic> lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in <jats:italic>FBP1<\/jats:italic> and <jats:italic>ACAD9<\/jats:italic> might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1151166","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T05:42:26Z","timestamp":1686721346000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism (FBP1, ACAD9) and vesicle trafficking 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