Agrebi Nourhen, Mackeh Rafah, Alsabbagh Mohamed, Elmi Asha, Al-Marri Amnah A, Hubrack Satanay Z, Purayil Saleema C, Karim Mohammed Yousuf, Hassan Amel, Lo Bernice
Translational Medicine Department, Research Department, Sidra Medicine, Doha, Qatar.
Allergy & Immunology Division, Department of Medicine, Hamad Medical Corporation, Doha, Qatar.
Front Immunol. 2025 Jun 2;16:1594636. doi: 10.3389/fimmu.2025.1594636. eCollection 2025.
Hyper-IgM syndrome (HIGM) is a genetic immunodeficiency characterized by elevated to normal IgM levels and decreased IgG, IgA, and IgE. The overlapping clinical presentations of different gene mutations complicate diagnosis and management.
This study aims to elucidate the clinical implications of concurrent and homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome.
We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the and genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of and mutations and to provide a definitive diagnosis and appropriate management.
Genetic analysis identified two homozygous variants: (p.W80S) and (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation.
The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the p.W80S variant is pathogenic, while the p.R77Q variant is likely benign.
高IgM综合征（HIGM）是一种遗传性免疫缺陷病，其特征为IgM水平升高至正常，而IgG、IgA和IgE水平降低。不同基因突变的重叠临床表现使诊断和管理变得复杂。
本研究旨在阐明一名诊断为高IgM综合征的儿科患者中同时存在的纯合变异的临床意义。
我们对一名突尼斯患者进行了免疫学和基因分析，该患者在 和 基因中存在两个意义未明的纯合变异（VUS），怀疑其导致高IgM和免疫缺陷。我们进行了功能测试，以确定 和 突变的致病性，并提供明确的诊断和适当的管理。
基因分析鉴定出两个纯合变异： （p.W80S）和 （p.R77Q）。免疫表型分析和功能研究发现，类别转换记忆B细胞和体细胞超突变大大减少，但T细胞反应和NFkB激活正常。
多个纯合VUS的同时存在凸显了对高度近亲结婚患者进行基因诊断的重大挑战。需要进行功能检查以及家系分离研究，以阐明变异的致病性，并为这些患者提供明确的诊断和量身定制的治疗策略。我们的研究表明， 基因的p.W80S变异是致病性的，而 基因的p.R77Q变异可能是良性的。
