AUTHOR=Brauer Nina , Maruta Yuto , Lisci Miriam , Strege Katharina , Oschlies Ilske , Nakamura Hikari , Böhm Svea , Lehmberg Kai , Brandhoff Leon , Ehl Stephan , Parvaneh Nima , Klapper Wolfram , Fukuda Mitsunori , Griffiths Gillian M. , Hennies Hans Christian , Niehues Tim , Ammann Sandra 

TITLE=Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism (FBP1, ACAD9) and vesicle trafficking (RAB27A)

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1151166

DOI=10.3389/fimmu.2023.1151166

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><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).</p></sec><sec><title>Methods and results</title><p>Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in <italic>RAB27A</italic>, <italic>FBP1 (</italic>Fructose-1,6-bisphosphatase 1<italic>)</italic> and <italic>ACAD9 (</italic>Acyl-CoA dehydrogenase family member 9<italic>).</italic> Variants in <italic>RAB27A</italic> lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition.</p></sec><sec><title>Discussion</title><p>Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in <italic>FBP1</italic> and <italic>ACAD9</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.</p></sec>