FHL3
MCID: HMP013
MIFTS: 42

Hemophagocytic Lymphohistiocytosis, Familial, 3 (FHL3)

Categories: Blood diseases, Genetic diseases, Immune diseases, Liver diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Hemophagocytic Lymphohistiocytosis, Familial, 3

MalaCards integrated aliases for Hemophagocytic Lymphohistiocytosis, Familial, 3:

Name: Hemophagocytic Lymphohistiocytosis, Familial, 3 56 13 71
Familial Hemophagocytic Lymphohistiocytosis 3 12 73 29 6 15
Hplh3 56 12 73
Fhl3 56 12 73
Hlh3 56 12 73
Lymphohistiocytosis, Hemophagocytic, Familial, Type 3 39

Characteristics:

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy


HPO:

31
hemophagocytic lymphohistiocytosis, familial, 3:
Inheritance autosomal recessive inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0110923
OMIM 56 608898
OMIM Phenotypic Series 56 PS267700
MeSH 43 D051359
MedGen 41 C1837174
UMLS 71 C1837174

Summaries for Hemophagocytic Lymphohistiocytosis, Familial, 3

OMIM : 56 Secretion of the contents of cytolytic granules at the immunologic synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin (170280)-containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Familial hemophagocytic lymphohistiocytosis is a genetically heterogeneous condition characterized by defective cytotoxicity. For a more detailed description of FHL, see 267700. (608898)

MalaCards based summary : Hemophagocytic Lymphohistiocytosis, Familial, 3, also known as familial hemophagocytic lymphohistiocytosis 3, is related to hemophagocytic lymphohistiocytosis, familial, 1 and hemophagocytic lymphohistiocytosis. An important gene associated with Hemophagocytic Lymphohistiocytosis, Familial, 3 is UNC13D (Unc-13 Homolog D), and among its related pathways/superpathways are Deregulation of Rab and Rab Effector Genes in Bladder Cancer and wtCFTR and deltaF508 traffic / Late endosome and Lysosome (norm and CF). Affiliated tissues include bone marrow, bone and liver, and related phenotypes are anemia and granulocytopenia

Disease Ontology : 12 A hemophagocytic lymphohistiocytosis that has material basis in a mutation of UNC13D on chromosome 17q25.1.

UniProtKB/Swiss-Prot : 73 Familial hemophagocytic lymphohistiocytosis 3: A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia.

Related Diseases for Hemophagocytic Lymphohistiocytosis, Familial, 3

Diseases in the Hemophagocytic Lymphohistiocytosis family:

Hemophagocytic Lymphohistiocytosis, Familial, 1 Hemophagocytic Lymphohistiocytosis, Familial, 4
Hemophagocytic Lymphohistiocytosis, Familial, 2 Hemophagocytic Lymphohistiocytosis, Familial, 3
Hemophagocytic Lymphohistiocytosis, Familial, 5 Secondary Hemophagocytic Lymphohistiocytosis
Primary Hemophagocytic Lymphohistiocytosis

Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 3 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 31)
# Related Disease Score Top Affiliating Genes
1 hemophagocytic lymphohistiocytosis, familial, 1 29.8 UNC13D SYS1 STX11 SH2D1A RAB27A
2 hemophagocytic lymphohistiocytosis 29.8 UNC13D UNC13B STX11 SH2D1A RAB27A
3 glycogen storage disease vii 11.2
4 retinitis pigmentosa 37 11.2
5 acute stress disorder 11.2
6 glioma 10.4
7 glial tumor 10.4
8 breast cancer 10.1
9 hepatocellular carcinoma 10.1
10 pancreatic cancer 10.1
11 autosomal recessive disease 10.1
12 brain glioma 10.1
13 glioblastoma multiforme 10.1
14 astrocytoma 10.1
15 malignant glioma 10.1
16 pancreatic ductal adenocarcinoma 10.1
17 primary hemophagocytic lymphohistiocytosis 10.0 UNC13D STX11 RAB27A
18 mirror agnosia 10.0 FSCN1 CES1
19 macrophage activation syndrome 10.0 UNC13D RAB27A
20 piebald trait 9.9 UNC13D STX11 RAB27A
21 hemophagocytic lymphohistiocytosis, familial, 4 9.9 UNC13D UNC13B STX11 RAB27A
22 acute hemorrhagic encephalitis 9.8 UNC13D STX11 SH2D1A
23 lymphoproliferative syndrome 1 9.8 UNC13D STX11 SH2D1A
24 hermansky-pudlak syndrome 9.6 UNC13D STX11 RAB27A
25 lymphoproliferative syndrome, x-linked, 2 9.6 UNC13D STX11 SH2D1A RAB27A
26 lymphoproliferative syndrome, x-linked, 1 9.6 UNC13D STX11 SH2D1A RAB27A
27 griscelli syndrome, type 2 9.6 UNC13D STX11 SH2D1A RAB27A
28 chediak-higashi syndrome 9.5 UNC13D STX11 SH2D1A RAB27A
29 hemophagocytic lymphohistiocytosis, familial, 2 9.5 UNC13D SYS1 STX11 SH2D1A CES1
30 pancytopenia 9.5 UNC13D STX11 SH2D1A RAB27A
31 griscelli syndrome 9.4 UNC13D UNC13B STX11 SH2D1A RAB27A

Graphical network of the top 20 diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 3:



Diseases related to Hemophagocytic Lymphohistiocytosis, Familial, 3

Symptoms & Phenotypes for Hemophagocytic Lymphohistiocytosis, Familial, 3

Human phenotypes related to Hemophagocytic Lymphohistiocytosis, Familial, 3:

31 (show all 8)
# Description HPO Frequency HPO Source Accession
1 anemia 31 very rare (1%) HP:0001903
2 granulocytopenia 31 very rare (1%) HP:0001913
3 reduced natural killer cell activity 31 very rare (1%) HP:0012178
4 fever 31 HP:0001945
5 hypertriglyceridemia 31 HP:0002155
6 hepatosplenomegaly 31 HP:0001433
7 hemophagocytosis 31 HP:0012156
8 hypofibrinogenemia 31 HP:0011900

Symptoms via clinical synopsis from OMIM:

56
Laboratory Abnormalities:
hypertriglyceridemia
low fibrinogen levels

Abdomen Liver:
hepatosplenomegaly
liver dysfunction

Immunology:
overwhelming activation of t lymphocytes and macrophages associated with fever
activated (hla dr+) cd8+ t lymphocytes in peripheral blood
defective anti cd3-driven cytotoxic t-cell activity

Hematology:
pancytopenia
hemophagocytosis (in bone marrow or cerebrospinal fluid)

Abdomen Spleen:
hepatosplenomegaly

Clinical features from OMIM:

608898

MGI Mouse Phenotypes related to Hemophagocytic Lymphohistiocytosis, Familial, 3:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 nervous system MP:0003631 9.28 APAF1 ASCL1 FSCN1 KIRREL2 RAB27A SCYL3

Drugs & Therapeutics for Hemophagocytic Lymphohistiocytosis, Familial, 3

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Maximizing Mechanisms of Muscle Hypertrophy to Combat Sarcopenia in Older Adults Completed NCT02442479

Search NIH Clinical Center for Hemophagocytic Lymphohistiocytosis, Familial, 3

Genetic Tests for Hemophagocytic Lymphohistiocytosis, Familial, 3

Genetic tests related to Hemophagocytic Lymphohistiocytosis, Familial, 3:

# Genetic test Affiliating Genes
1 Familial Hemophagocytic Lymphohistiocytosis 3 29 UNC13D

Anatomical Context for Hemophagocytic Lymphohistiocytosis, Familial, 3

MalaCards organs/tissues related to Hemophagocytic Lymphohistiocytosis, Familial, 3:

40
Bone Marrow, Bone, Liver, T Cells, Endothelial

Publications for Hemophagocytic Lymphohistiocytosis, Familial, 3

Articles related to Hemophagocytic Lymphohistiocytosis, Familial, 3:

# Title Authors PMID Year
1
Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. 6 56
16825436 2006
2
Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. 56 6
16278825 2006
3
Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). 6 56
14622600 2003
4
Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. 56
17993578 2008
5
Hemophagocytic Lymphohistiocytosis, Familial – ARCHIVED CHAPTER, FOR HISTORICAL REFERENCE ONLY 6
20301617 2006
6
A novel Munc13-4/S100A10/annexin A2 complex promotes Weibel-Palade body exocytosis in endothelial cells. 61
28450451 2017
7
The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. 61
24470399 2014

Variations for Hemophagocytic Lymphohistiocytosis, Familial, 3

ClinVar genetic disease variations for Hemophagocytic Lymphohistiocytosis, Familial, 3:

6 (show top 50) (show all 280) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 UNC13D NM_199242.2(UNC13D):c.2346_2349del (p.Arg782fs)deletion Pathogenic 420155 rs764196809 17:73830174-73830177 17:75834093-75834096
2 UNC13D NM_199242.2(UNC13D):c.118-308C>TSNV Pathogenic 533095 rs959968589 17:73839908-73839908 17:75843827-75843827
3 UNC13D NM_199242.2(UNC13D):c.1472T>A (p.Leu491Ter)SNV Pathogenic 533091 rs1555601754 17:73832165-73832165 17:75836084-75836084
4 UNC13D NM_199242.2(UNC13D):c.2293G>T (p.Glu765Ter)SNV Pathogenic 580834 rs763117746 17:73830411-73830411 17:75834330-75834330
5 UNC13D NM_199242.2(UNC13D):c.1768C>T (p.Gln590Ter)SNV Pathogenic 573522 rs1567818774 17:73831570-73831570 17:75835489-75835489
6 UNC13D NM_199242.2(UNC13D):c.3011_3014dup (p.Tyr1006fs)duplication Pathogenic 569875 rs1567816070 17:73825004-73825005 17:75828923-75828924
7 UNC13D NM_199242.2(UNC13D):c.2258_2267delinsTACCTTGTCCGA (p.Gly753fs)indel Pathogenic 566475 rs1567818219 17:73830437-73830446 17:75834356-75834365
8 UNC13D NM_199242.2(UNC13D):c.520C>T (p.Gln174Ter)SNV Pathogenic 664792 17:73838563-73838563 17:75842482-75842482
9 UNC13D NM_199242.3(UNC13D):c.865_877dup (p.Arg293fs)duplication Pathogenic 848121 17:73836172-73836173 17:75840091-75840092
10 UNC13D NM_199242.3(UNC13D):c.1650del (p.Glu551fs)deletion Pathogenic 839231 17:73831805-73831805 17:75835724-75835724
11 UNC13D NM_199242.3(UNC13D):c.1215C>G (p.Tyr405Ter)SNV Pathogenic 870593 17:73832736-73832736 17:75836655-75836655
12 UNC13D NM_199242.2(UNC13D):c.1828_1839del (p.Arg610_Gln613del)deletion Pathogenic 1996 rs796065024 17:73831499-73831510 17:75835418-75835429
13 UNC13D NM_199242.2(UNC13D):c.216del (p.Asn73fs)deletion Pathogenic 1997 rs796065025 17:73839285-73839285 17:75843204-75843204
14 UNC13D NM_199242.2(UNC13D):c.1754dup (p.His586fs)duplication Pathogenic 1998 rs796065026 17:73831583-73831584 17:75835502-75835503
15 UNC13D NM_199242.2(UNC13D):c.1389+1G>ASNV Pathogenic 1999 rs777759523 17:73832419-73832419 17:75836338-75836338
16 UNC13D NM_199242.2(UNC13D):c.766C>T (p.Arg256Ter)SNV Pathogenic 2000 rs121434352 17:73836398-73836398 17:75840317-75840317
17 UNC13D NM_199242.2(UNC13D):c.753+1G>TSNV Pathogenic 2001 rs201908137 17:73836587-73836587 17:75840506-75840506
18 UNC13D NM_199242.2(UNC13D):c.1208T>C (p.Leu403Pro)SNV Pathogenic 2002 rs121434353 17:73832743-73832743 17:75836662-75836662
19 UNC13D NM_199242.2(UNC13D):c.2570T>G (p.Phe857Cys)SNV Pathogenic 2003 rs121434354 17:73827234-73827234 17:75831153-75831153
20 UNC13D NM_199242.2(UNC13D):c.2695C>T (p.Arg899Ter)SNV Pathogenic 325247 rs766657895 17:73826673-73826673 17:75830592-75830592
21 UNC13D NM_199242.3(UNC13D):c.2955-1G>ASNV Likely pathogenic 849686 17:73825065-73825065 17:75828984-75828984
22 UNC13D NM_199242.3(UNC13D):c.321+1_321+2deldeletion Likely pathogenic 837222 17:73839093-73839094 17:75843012-75843013
23 UNC13D NM_199242.2(UNC13D):c.2447+1G>ASNV Likely pathogenic 639780 17:73829046-73829046 17:75832965-75832965
24 UNC13D NM_199242.2(UNC13D):c.859-1G>CSNV Likely pathogenic 651539 17:73836192-73836192 17:75840111-75840111
25 UNC13D NM_199242.2(UNC13D):c.569+5G>ASNV Likely pathogenic 647023 17:73838509-73838509 17:75842428-75842428
26 UNC13D NM_199242.2(UNC13D):c.498del (p.Glu167fs)deletion Likely pathogenic 804423 17:73838585-73838585 17:75842504-75842504
27 UNC13D NM_199242.2(UNC13D):c.247C>T (p.Arg83Ter)SNV Likely pathogenic 631788 rs1274685768 17:73839254-73839254 17:75843173-75843173
28 UNC13D NM_199242.2(UNC13D):c.1299-1G>ASNV Likely pathogenic 440775 rs1555601863 17:73832511-73832511 17:75836430-75836430
29 UNC13D NM_199242.2(UNC13D):c.2709+1G>ASNV Likely pathogenic 440834 rs1555600214 17:73826658-73826658 17:75830577-75830577
30 UNC13D NM_199242.2(UNC13D):c.1727+1G>ASNV Likely pathogenic 533098 rs754882266 17:73831727-73831727 17:75835646-75835646
31 UNC13D NM_199242.2(UNC13D):c.227C>T (p.Thr76Met)SNV Conflicting interpretations of pathogenicity 533092 rs78028658 17:73839274-73839274 17:75843193-75843193
32 UNC13D NM_199242.2(UNC13D):c.2983G>C (p.Ala995Pro)SNV Conflicting interpretations of pathogenicity 464457 rs138760432 17:73825036-73825036 17:75828955-75828955
33 UNC13D NM_199242.2(UNC13D):c.2542A>C (p.Ile848Leu)SNV Conflicting interpretations of pathogenicity 464455 rs144968313 17:73827335-73827335 17:75831254-75831254
34 UNC13D NM_199242.2(UNC13D):c.2553+5C>GSNV Conflicting interpretations of pathogenicity 533109 rs201930023 17:73827319-73827319 17:75831238-75831238
35 UNC13D NM_199242.3(UNC13D):c.2335G>A (p.Val779Met)SNV Conflicting interpretations of pathogenicity 403593 rs113861754 17:73830188-73830188 17:75834107-75834107
36 UNC13D NM_199242.2(UNC13D):c.1131C>G (p.Ser377Arg)SNV Conflicting interpretations of pathogenicity 759815 17:73832924-73832924 17:75836843-75836843
37 UNC13D NM_199242.2(UNC13D):c.1890G>A (p.Ala630=)SNV Conflicting interpretations of pathogenicity 800079 17:73831103-73831103 17:75835022-75835022
38 UNC13D NM_199242.2(UNC13D):c.610A>G (p.Met204Val)SNV Conflicting interpretations of pathogenicity 574872 rs144722609 17:73837042-73837042 17:75840961-75840961
39 UNC13D NM_199242.2(UNC13D):c.811C>T (p.Pro271Ser)SNV Conflicting interpretations of pathogenicity 719448 17:73836353-73836353 17:75840272-75840272
40 UNC13D NM_199242.2(UNC13D):c.114G>A (p.Pro38=)SNV Conflicting interpretations of pathogenicity 721239 17:73840305-73840305 17:75844224-75844224
41 UNC13D NM_199242.2(UNC13D):c.1215C>T (p.Tyr405=)SNV Conflicting interpretations of pathogenicity 749676 17:73832736-73832736 17:75836655-75836655
42 UNC13D NM_199242.2(UNC13D):c.629T>G (p.Val210Gly)SNV Conflicting interpretations of pathogenicity 742017 17:73836897-73836897 17:75840816-75840816
43 UNC13D NM_199242.2(UNC13D):c.3078C>T (p.Pro1026=)SNV Conflicting interpretations of pathogenicity 263239 rs372034111 17:73824941-73824941 17:75828860-75828860
44 UNC13D NM_199242.2(UNC13D):c.2588G>A (p.Gly863Asp)SNV Conflicting interpretations of pathogenicity 225509 rs140184929 17:73827216-73827216 17:75831135-75831135
45 UNC13D NM_199242.2(UNC13D):c.1228A>C (p.Ile410Leu)SNV Conflicting interpretations of pathogenicity 225510 rs117221419 17:73832723-73832723 17:75836642-75836642
46 UNC13D NM_199242.2(UNC13D):c.99G>A (p.Pro33=)SNV Conflicting interpretations of pathogenicity 263249 rs147886860 17:73840320-73840320 17:75844239-75844239
47 UNC13D NM_199242.2(UNC13D):c.24G>A (p.Pro8=)SNV Conflicting interpretations of pathogenicity 263227 rs143320460 17:73840395-73840395 17:75844314-75844314
48 UNC13D NM_199242.2(UNC13D):c.175G>A (p.Ala59Thr)SNV Conflicting interpretations of pathogenicity 263219 rs9904366 17:73839326-73839326 17:75843245-75843245
49 UNC13D NM_199242.2(UNC13D):c.2002C>T (p.Arg668Cys)SNV Conflicting interpretations of pathogenicity 325258 rs376137910 17:73830788-73830788 17:75834707-75834707
50 UNC13D NM_199242.2(UNC13D):c.972C>T (p.Asp324=)SNV Conflicting interpretations of pathogenicity 325268 rs368990813 17:73836003-73836003 17:75839922-75839922

Expression for Hemophagocytic Lymphohistiocytosis, Familial, 3

Search GEO for disease gene expression data for Hemophagocytic Lymphohistiocytosis, Familial, 3.

Pathways for Hemophagocytic Lymphohistiocytosis, Familial, 3

Pathways related to Hemophagocytic Lymphohistiocytosis, Familial, 3 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.16 UNC13D RAB27A
2 9.7 UNC13D RAB27A

GO Terms for Hemophagocytic Lymphohistiocytosis, Familial, 3

Cellular components related to Hemophagocytic Lymphohistiocytosis, Familial, 3 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cytosol GO:0005829 9.7 UNC13D UNC13B UBP1 SYS1 SNAI1 SH2D1A
2 exocytic vesicle GO:0070382 9.16 UNC13D RAB27A
3 Weibel-Palade body GO:0033093 8.62 UNC13D RAB27A

Biological processes related to Hemophagocytic Lymphohistiocytosis, Familial, 3 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 positive regulation of exocytosis GO:0045921 9.26 UNC13D RAB27A
2 natural killer cell degranulation GO:0043320 9.16 UNC13D RAB27A
3 positive regulation of regulated secretory pathway GO:1903307 8.96 UNC13D RAB27A
4 exocytosis GO:0006887 8.92 UNC13D UNC13B STX11 RAB27A

Sources for Hemophagocytic Lymphohistiocytosis, Familial, 3

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
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32 ICD10
33 ICD10 via Orphanet
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57 OMIM via Orphanet
61 PubMed
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68 SNOMED-CT via HPO
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72 UMLS via Orphanet
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