Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis

@article{Horne2008CharacterizationOP,
  title={Characterization of PRF1, STX11 and UNC13D genotype‐phenotype correlations in familial hemophagocytic lymphohistiocytosis},
  author={AnnaCarin Horne and Kim G{\"o}ransdotter Ramme and Eva Rudd and Chengyun Zheng and Yasser Wali and Zakia al-Lamki and Aytemiz G{\"u}rgey and Nevin Yalman and Magnus Nordenskj{\"o}ld and Jan-Inge Henter},
  journal={British Journal of Haematology},
  year={2008},
  volume={143}
}
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease‐causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype‐phenotype study in a large, multi‐ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in… 
Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).
TLDR
The largest cohort of patients with FHL5 so far is reported, an extended disease spectrum is described, a clear genotype-phenotype correlation is demonstrated, and mutations affecting 1 of the exon 15 splice sites are detected for the first time.
Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP
TLDR
The present study describes a distinct variant spectrum in Chinese patients with HLH, whereby UNC13D is the most frequently mutated gene with missense variants that are the most common molecular defects.
Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.
TLDR
Familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes, and mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.
UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis
TLDR
The identification of mutations missed by conventional sequencing would better delineate the mutation spectrum and help to establish the optimal molecular diagnostic strategy for familial hemophagocytic lymphohistiocytosis in Korea, which might need an RNA-based screening strategy.
Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D.
TLDR
Findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3, which is an autosomal recessive, often-fatal hyperinflammatory disorder.
Exome sequencing for simultaneous mutation screening in children with hemophagocytic lymphohistiocytosis
TLDR
Exome sequencing demonstrated the ability to identify rare genetic variants in HLH patients and is useful in the detection of mutations in multi-gene associated diseases.
Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis (FHL) patients in India.
TLDR
A wide heterogeneity was observed in the nature of mutations in Indian FHL2 patients and molecular characterization of PRF1 gene was not only used in the confirmation of diagnosis but also in genetic counseling and pre-natal diagnosis in affected families.
RF1 Gene Mutation in Familial Hemophagocytic Lymphohistiocytosis 2: A Family Report and Literature Review
  • Yuan Shi, Zhidong Qiao, +4 authors Guanglu Yang
  • Pharmacogenomics and Personalized Medicine
  • 2021
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
Novel Syntaxin 11 Gene (STX11) Mutation in Three Argentinean Patients with Hemophagocytic Lymphohistiocytosis
TLDR
Each parent from three unrelated families resulted heterozygous for this deletion confirming the diagnosis of familial hemophagocytic lymphohistiocytosis type 4, and genotyping at ten microsatellites surrounding this gene support the presence of a single-haplotype block carrying the novel mutation.
STX11‐deficient familial hemophagocytic lymphohistiocytosis type 4 is associated with self‐resolving flares and a milder clinical course
TLDR
A previously healthy 18-month-old male child with no relevant family history presented with 10 days of fever and diarrhea, and was found to have pancytopenia and massive splenomegaly on admission, prompting a working diagnosis of primary ALPS with a possible secondary HLH-like inflammatory episode.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 47 REFERENCES
Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A
TLDR
The findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D and prevent the formation of a stable hMunc13‐4/Rab27a complex in vitro.
Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis
TLDR
Control assessment of perforin expression and cytotoxic assays by lymphocytes from young children led to the conclusion that per forin content of natural killer cells could be a reliable diagnostic test at any age.
Genotype–phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations
TLDR
Genotype–phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide, finding specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups.
Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.
TLDR
The combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the F HL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of theFHL cases are caused by mutations in not-yet-identified genes.
Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies
TLDR
The results suggest that STX11 gene mutations may be associated with secondary malignancies (MDS/AML), and that there is segregation of specific clinical features in FHL patients with an underlying genotype.
Novel Munc13–4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis
TLDR
Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.
Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11.
TLDR
It is concluded that, besides mutations in perforin 1, defects in the endocytosis or the exocytotic pathway may be a common mechanism in FHL.
Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes
TLDR
MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway and the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some F HL3 patients.
An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression
TLDR
A novel perforin variant in the homozygous state in an Omani boy who was diagnosed 44 days after birth is reported, which confirms that drastic reduction in its expression is not a constant feature in familial hemophagocytic lymphohistiocytosis type 2.
Clinical and Genetic Studies of Familial Hemophagocytic Lymphohistiocytosis in Oman: Need for Early Treatment
TLDR
A nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed, and a novel missense mutation in the perforin gene was identified, causing a transition of proline to threonine at codon 89.
...
1
2
3
4
5
...