Novel Mutations in the UNC13D Gene Carried by a Chinese Neonate with Hemophagocytic Lymphohistiocytosis

Chen, Yuanyuan; Cheng, Yufei; Tang, Yuanyue

doi:10.3349/ymj.2013.54.4.1053

Cited by 10 publications

(11 citation statements)

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“…Five missense mutations of UNC13D gene (Additional file 2 : Figure S2), c.478G>A (p.Val160 Met) in P3 , c.518C>T (p.Thr173Met) in P4 , c.760C>T (p.Arg254Cys) in P5 , c.3259C>T (p.Arg1087Trp) in P7 , and c.118-307G>A in P45 , were found in four males and one female, respectively. Another heterozygous mutation c.2296C>T (p.Glu766Ter) in exon23 of UNC13D gene of an 8-day male patient ( P6 ), with the cDNA study revealed that this mutation had a deleterious effect on splicing, c.2295_2298delGCAG (p.Glu765Aspfs*27) (Additional file 6 : Figure S6), was already reported by our group as a special case [ 25 ]. Two heterozygous mutations of STXBP2 gene, c.575G>A (p.Arg192His), and c.767T>C (p.Leu256Pro), were identified in two patients (Additional file 3 : Figure S3).…”

Section: Resultsmentioning

confidence: 68%

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

et al. 2016

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BackgroundHaemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation, and HLH patients with mutations in genes including PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP, and ITK were reported to be primary HLH. Due to the different treatment options, the differentiation between primary and secondary HLH is critical. Our previous studies have showed that a Th1/Th2 cytokine profile is diagnostic for HLH, yet the cytokine profiles between primary and secondary HLH have not been compared. The aim of the study was to test whether the Th1/Th2 cytokine profile could be used as a tool to differentiate between primary and secondary HLH.MethodsA total of 45 hospitalized Chinese children with HLH during the period of February 2010 through September 2012 were enrolled in the study. Fifty healthy children were enrolled as controls. Primary HLH related genes were sequenced using genomic DNA samples. The Th1/Th2 cytokine levels including interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10, IL-6, IL-4 and IL-2 were quantitatively determined by cytometric bead assay techniques.ResultsPrimary HLH group (n = 4) included one patient with biallelic heterozygous mutations in PRF1 gene, and three patients with hemizygous mutation in SH2D1A gene. Based on the available genetic data, the other 41 patients were classified into the secondary HLH group. When compared the cytokine levels between the two groups, IL-4 level in primary-HLH was significantly lower than that in secondary HLH (P = 0.025), while IFN-γ level in primary HLH had a tendency of statistically lower than that in secondary HLH (P = 0.051). Area under receiver operating characteristic (ROC) curves of IL-4 and IFN-γ, IL-10, TNF-α, IL-2, and IL-6 levels were 0.841, 0.799, 0.506, 0.494, 0.457, and 0.250, respectively. ROC curves showed that 1.7 pg/ml of IL-4 had sensitivity and specificity for differentiation between primary and secondary HLH as 70.7 and 100.0 %, while 433.9 pg/ml of IFN-γ had sensitivity and specificity as 51.2 and 100.0 %, respectively.ConclusionsHLH patients with lower IL-4 and IFN-γ levels have higher possibility to be primary HLH. The cytokine profile may be used as an additional tool for the quick differential diagnosis between primary and secondary HLH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13052-016-0262-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 68%

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

et al. 2016

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“…As we all known, FHL is an autosomal recessive disorder, but whether an autosomal dominant trait in FHL patients exists or not has not been identified [36]. The fact that several FHL cases had only one UNC13D mutant allele demonstrated that conventional direct sequencing missed the other mutation [37].…”

Section: Discussionmentioning

confidence: 97%

Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis

et al. 2015

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A 32-year-old man of non-consanguineous Chinese parentage, with high-grade fever, rash, joint pain, nausea, and vomiting, was diagnosed as adult-onset still's disease at his initial admission. Although prednisone had been taken, the patient presented with recurrent high-grade fever, rash, splenomegaly, hypertriglyceridemia, cryptogenic hepatitis, apparently elevated levels of serum ferritin(>20,000 μg/L), which met the proposed HLH diagnostic criteria, 2009. Sequence analysis of genomic DNA from the patient's peripheral blood demonstrated heterozygous for UNC13D mutation: c. 1232 G>A, and AP3B1 mutation: c. 1075 A>G, which were predicted to be pathogenic. Unfortunately, at the time, molecular confirmation results for HLH were obtained, and this patient had died from progressive HLH disease with multiple organ dysfunction syndrome caused by shock. FHL should be considered in the differential diagnosis of adults who present with adult-onset still's disease-like symptoms.

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“…50,51 Compound heterozygous mutations in FHL patients are prevalent, as such mutations have been previously reported in the UNC13D gene. 52 Nevertheless, homozygous mutations are common in populations with consanguineous marriage. 53 We indicated that compound heterozygous and homozygous mutations occurred in approximately 48% and 37% of patients with FHL3, respectively.…”

Section: Discussionmentioning

confidence: 99%

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review

Amirifar

Ranjouri

Abolhassani

et al. 2020

Pediatric Allergy Immunology

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Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive immune disorder that is caused by mutations in 6 different genes related to the formation and function of secretory lysosomes within cytotoxic T lymphocytes and natural killer (NK) cells. Thus, defect in these genes is associated with the accumulation of antigens due to defective cytotoxic function. FHL type 3 (FHL3) accounts for nearly 30-40% of FHL, and its underlying reason is mutation in UNC13D gene which encodes Munc13-4 protein. Methods: For the first time, we aimed to systematically review clinical features, immunologic data, and genetic findings of patients with FHL3. We conducted electronic searches for English-language articles in PubMed, Web of Science, EMBASE, and Scopus databases to collect comprehensive records related to patients with UNC13D mutations. Results: A total of 279 abstracts were initially reviewed for inclusion. Among them, 57 articles corresponding to 322 individual FHL3 patients fulfilled our selection criteria. Finally, 73 and 249 patients were considered as severe and mild feature groups, respectively. Our results confirmed that fever, hepatosplenomegaly, and hemophagocytosis are common clinical features in the disease. Moreover, reduced fibrinogen and NK cell activity, as well as increased ferritin and triglycerides, are important markers for early diagnosis of the FHL3 disease. Investigation of genotype showed that the most prevalent type and zygosity of UNC13D are splice-site errors and compound heterozygous, respectively. Conclusion: FHL3 patients have a wide range of clinical manifestations, which makes it difficult to diagnose. Therefore, it seems that the sequencing of the entire UNC13D gene (coding and non-coding regions) is the most appropriate way to accurate diagnosis of FHL3 patients. | 187 AMIRIFAR et Al.

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Novel Mutations in the UNC13D Gene Carried by a Chinese Neonate with Hemophagocytic Lymphohistiocytosis

Cited by 10 publications

References 13 publications

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis

Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review

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