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Whole exome sequencing reveals a novel LRBA mutation and clonal hematopoiesis in a common variable immunodeficiency patient presented with hemophagocytic lymphohistiocytosis


Common variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.

Letter to the Editor,

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing and highly fatal disease, and the prognosis is closely related to the treatment of the primary disease [1], so it is particularly important to actively search for the cause while treating HLH. Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency disorder with heterogeneous phenotype and genotype [2], a timely and accurate diagnosis is also urgent to prevent significant morbidity and mortality [3]. Here, we report an adult CVID patient manifested as HLH, whole exome sequencing (WES) revealed LPS-responsive beige-like anchor (LRBA) and myeloid malignancy associated mutations may be the genetic cause. Finally, hematopoietic stem cell transplantation (HSCT) saved her from severe cytopenia and immune deficiency.

A 46 years old female patient who presented with fever and fatigue as well as cytopenia for 20 days was referred to our center, physical examinations showed significantly hepatosplenomegaly. Laboratory tests revealed low fibrinogen and elevated ferritin and soluble CD25. Bone marrow smear showed an increase of phagocytosis (Fig 1A). Flow cytometry showed increased abnormal granulocytes of 76.45% (Fig 1B), while biopsy showed proliferative hematopoiesis with dysplastic erythroid and increased immature cells (Fig 1C). Hypogammaglobinemia and abnormal T cell subpopulations of peripheral blood were also detected (Table 1). Image test suggested pneumonia but no evidence of malignancy (Additional file 1: Figure S1). Therefore, the diagnosis of HLH is established. Viral infections were excluded by negative serology results. Her previous history showed recurrent respiratory tract infection, severe human papilloma virus infection led to total hysterectomy and severe virus pneumonia which needed ventilator adjuvant treatment. Unexplained hepatosplenomegaly and hypogammaglobinemia was found then, but no severe cytopenia, thus CVID was established. WES analysis detected a novel single heterozygous mutation of LRBA (c.1876T > C; p.W626R). Another 4 somatic mutations which suggested clonal hematopoiesis were also identified: ASXL1(c.1967dupA); PTPN11(c.226G > A); U2AF1(c.101C > T and c.470A > G). After obtaining the informed consent, the same mutation of LRBA in her healthy father, little brother and her son were confirmed by Sanger sequencing, but no such mutation in her mother and the older brother (Fig 1D).

Fig. 1
figure 1

Bone marrow features: A Phagocytosis of red cells and platelets by hemophagocytichistiocytes; B Abnormal granulocytes and blast by flow cytometry; C Immunochemistry of BM specimen suggested an increase in immature myeloid cells which are positive for CD33, CD117, CD45-SSA, and CD11B; D Pedigree of the family and Sanger sequencing confirming the mutation status of LRBA in the patient and her parent, brother and son (F, father; M, mother; Patient; S, Son; B1, brother 1; B2,brother 2)

Table 1 Immunological parameters

According to the HLH-2004 protocol, glucocorticoid and etoposide was given to her. Her fever improved and the spleen was significantly shrinked, but she still had cytopenia. On July 14th 2020, she underwent haploindentical allogeneic HSCT from her older brother. Until the time of writing this article, the patient showed normal blood cell count, close to normal immunoglobulin except for low IGA, no mutations were detected for another WES analysis.

Homozygous and compound heterozygous mutations of LRBA were identified as one cause of CVID recently, which could decrease or abolish LRBA protein expression, thus resulting in very low cytotoxic T lymphocyte–associated antigen 4 (CTLA4) expression and dysfunction of T cells [4]. Some researchers believed that mild phenotypes were associated with compound heterozygous mutations and residual protein expression of LRBA, while other research showed that LRBA protein expression levels are not correlated with clinical phenotypes [5, 6].Unfortunately, we have not tested the protein expression of LRBA in time, the T-to-C transition at position c.1876 in exon 14 of LRBA caused a substitution at position p. W626R(Cosmic 8925453), which was not in the main functional structural regions of the protein and we speculated that the novel mutation may be associated with LRBA structural instability and damaged regulatory function, just as reported by Pauline A et al., monoallelic LRBA mutation was disease associated [7]. Besides, possible polygenic and epigenetic factors could also involve in CVID pathogenesis, including PTPN11 [8, 9]. Just as in our case, mutations of ASXL1, U2AF1 and PTPN11 combined with LRBA may participate in the formation of clinical phenotype. Importantly, CVID patients had a higher risk of developing malignancies, mainly lymphoma, MDS were rarely reported [10]. Increased immature cells and dysplastic hematopoiesis as well as the detection of clonal marker such as mutations in ASXL1 and U2AF all suggested the diagnosis for MDS [11]. Moreover, after HLH had been effectively controlled, cytopenia was not improved, all prompting us to perform HSCT as soon as possible.

In conclusion, we report a rare case of patient with CVID manifested as HLH had LRBA mutation and clonal hematopoiesis. WES played an important role in etiology diagnosis and guiding treatment, thus should be considered in patients with atypical manifestations.

Availability of data and materials

The single institute data from this study is available from the corresponding author upon reasonable request.


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This work was supported by the National Natural Science Foundation of China grants (81700121, 81970117).

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Authors and Affiliations



YLR conceived the study, analyzed data, and drafted the manuscript. WL analyzed data. FC, XH and JHL collected and interpreted the data, XGW and XPZ followed the patient. JPL and HYT reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jianping Lan or Hongyan Tong.

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The study was approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (2020IIT 748th). Informed written consent was obtained from the patient for the studies conducted and for publication of any potentially identifiable images or data included in this article.

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Supplementary Information

Additional file 1: Figure S1.

A Scattered inflammation of both lungs and pleural effusion by chest CT scan. B PET-CT demonstrated enlargement of the spleen, mild increased FDG in the bone marrow and sinusitis.

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Ren, Y., Xiao, F., Cheng, F. et al. Whole exome sequencing reveals a novel LRBA mutation and clonal hematopoiesis in a common variable immunodeficiency patient presented with hemophagocytic lymphohistiocytosis. Exp Hematol Oncol 10, 38 (2021).

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