FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis

Viñas-Giménez, Laura; Padilla, Natàlia; Batlle-Masó, Laura; Casals, Ferrán; Rivière, Jacques G.; Martínez-Gallo, Mónica; Cruz, Xavier de la; Colobran, Roger

doi:10.3389/fimmu.2020.00107

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…The patient's reported STXBP2 VUS c.704G>A (p.Arg235Gln) is presented in a population database (rs757488006, 0.002%; ExAC) and the Invitae database. A VUS in the same amino acid has been reported previously, c.704G>C p.Arg235Pro, with a high likelihood score for pathogenicity ( 5 ). Pathogenicity prediction algorithms are controversial for the impact of this missense change (SIFT: “Deleterious”; PolyPhen-2: “Benign”; Align-GVGD: “Class C0”).…”

Section: Discussionsupporting

confidence: 67%

“…According to Janka and Stadt, as cited by George ( 3 ), FHL syndromes are subclassified into five subtypes (FHL-1 to FHL-5) based on the functional protein anomalies and the prerequisite genetic mutations. Viñas-Giménez et al ( 5 ) related four genes ( PRF1, UNC13D, STX11 , and STXBP2 ) in the 9q21.3–22 region that were identified as possible causes of FHL-2, FHL-3, FHL-4, and FHL-5, respectively. The mutated gene for the FHL-1 subtype is currently undefined.…”

Section: Introductionmentioning

confidence: 99%

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Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

et al. 2021

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Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, potentially fatal autosomal-recessive immunodeficiency, and STXBP2 mutations have been associated with FHL type 5 (FHL-5). Here, we report a case of a 2-year-old boy who presented with recurrent fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia since 4 months of age. His genetic analysis revealed a compound heterozygosity of the STXBP2 gene with a described pathogenic mutation, c.1247-1G>C (splicing acceptor site), harbored by his father and a likely pathogenic variant of uncertain significance (VUS), c.704G>A (p.Arg235Gln), harbored by his mother. He was diagnosed as compound heterozygous for FHL-5 and was treated with the HLH-2004 protocol. Since treatment, this patient has been in remission, and he is being evaluated for a hematopoietic stem cell transplantation (HSCT).

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

et al. 2021

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“…There were 433 different mutations of these genes to be found in the literature review, of which UNC13D had the maximum amount of mutations (189), followed by PRF1 (157), STXBP2 (66), and then STX11 (21). 9 …”

Section: Literature Reviewmentioning

confidence: 99%

RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review

Shi¹,

Qiao²,

Bi³

et al. 2021

PGPM

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Objective Gene mutation analysis was performed on a family with familial hemophagocytic lymphohistiocytosis (FHL) so as to provide an accurate etiological diagnosis, leading to genetic counseling for the family members. Methods The clinical data of two probands (siblings) with FHL in one family were analyzed, and eight genes related to the onset of the primary hemophagocytic lymphohistiocytosis (pHLH) ( PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4/XIAP, Rab27a, LYST ) were detected and analyzed in the probands and their parents with whole exome sequencing. Results Proband 1 was a two-year-old male with the clinical manifestations of fever, hepatosplenomegaly, and a decreased peripheral blood cell count, sCD25: 12504pg/mL. The results of genetic testing showed that there was a c.1349C>T heterozygous missense mutation and a c.853_855del heterozygous mutation in the PRF1 in proband 1. Proband 2 was an eight-year-old female with the clinical manifestations of convulsions and disturbance of consciousness with fever. The genetic test results were the same as those of proband 1. There was a single heterozygous mutation in the parents of the probands, and both probands had compound heterozygous mutations. Conclusion According to the clinical manifestations, laboratory tests, and results of the family molecular genetic testing, the probands could be clinically diagnosed as FHL2. The results of gene sequencing revealed that this was an autosomal recessive family with familial hemophagocytic syndrome. A rare pathogenic mutation (c.853_855del) in the PRF1 was discovered in the two patients with HLH.

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“…FHL2 resulted from mutations of the Perforin gene PRF1 , FHL3 from UNC13D/Munc13‐4 mutations, FHL4 from STX11 mutations and FHL5 from MUNC18‐2/STXBP2 mutations. A compendium of FHL genes, variants and literature is available at the publically accessible FHL database (https://www.biotoclin.org/FHLdb; Viñas‐Giménez et al, 2020). While PFR1 mutation would affect LGs' cytolytic activity directly, the other FHL subtypes stem from dysfunctional LG exocytosis that culminate in impaired target cell killing.…”

Section: Snares and Developmental Disorders Of The Immune Systemmentioning

confidence: 99%

SNAREs and developmental disorders

Tang

2020

Journal Cellular Physiology

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Members of the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) family mediate membrane fusion processes associated with vesicular trafficking and autophagy. SNAREs mediate core membrane fusion processes essential for all cells, but some SNAREs serve cell/tissue type‐specific exocytic/endocytic functions, and are therefore critical for various aspects of embryonic development. Mutations or variants of their encoding genes could give rise to developmental disorders, such as those affecting the nervous system and immune system in humans. Mutations to components in the canonical synaptic vesicle fusion SNARE complex (VAMP2, STX1A/B, and SNAP25) and a key regulator of SNARE complex formation MUNC18‐1, produce variant phenotypes of autism, intellectual disability, movement disorders, and epilepsy. STX11 and MUNC18‐2 mutations underlie 2 subtypes of familial hemophagocytic lymphohistiocytosis. STX3 mutations contribute to variant microvillus inclusion disease. Chromosomal microdeletions involving STX16 play a role in pseudohypoparathyroidism type IB associated with abnormal imprinting of the GNAS complex locus. In this short review, I discuss these and other SNARE gene mutations and variants that are known to be associated with a variety developmental disorders, with a focus on their underlying cellular and molecular pathological basis deciphered through disease modeling. Possible pathogenic potentials of other SNAREs whose variants could be disease predisposing are also speculated upon.

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FHLdb: A Comprehensive Database on the Molecular Basis of Familial Hemophagocytic Lymphohistiocytosis

Cited by 4 publications

References 34 publications

Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review

SNAREs and developmental disorders

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