Familial hemophagocytic lymphohistiocytosis type 1

Summary

Familial hemophagocytic lymphohistiocytosis type 1 (MONDO:0009974) is a disease with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include alemtuzumab, cyclophosphamide anhydrous, and rimiducid.

At a glance

• Cohort genes: 2
• ClinVar variants: 4
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hemophagocytic lymphohistiocytosis type 1
Mondo ID	MONDO:0009974
OMIM	267700
DOID	DOID:0110921
NCIT	C61276
UMLS	C4551514
MedGen	1642840
GARD	0006590
MedDRA	10070904
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis · familial hemophagocytic lymphohistiocytosis type 1 · familial HLH · FHL1 · hemophagocytic lymphohistiocytosis, familial, 1 · HLH1 · HPLH1

Data availability: 4 ClinVar variants · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › hereditary hemophagocytic lymphohistiocytosis › familial hemophagocytic lymphohistiocytosis type 1

Related subtypes (10): Chediak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis 4, familial hemophagocytic lymphohistiocytosis 2, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, familial hemophagocytic lymphohistiocytosis 3, familial hemophagocytic lymphohistiocytosis 5, Hermansky-Pudlak syndrome 9, hemophagocytic lymphohistiocytosis, familial, 6, hemophagocytic lymphohistiocytosis due to RhoG deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456031	NM_001159699.2(FHL1):c.576C>G (p.Tyr192Ter)	FHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13711	NM_001083116.3(PRF1):c.673C>T (p.Arg225Trp)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
239005	NM_001159699.2(FHL1):c.204+5C>T	FHL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
2921111	NM_001159699.2(FHL1):c.737-8C>G	FHL1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FHL1	Orphanet:178461	X-linked myopathy with postural muscle atrophy
FHL1	Orphanet:431272	X-linked scapuloperoneal muscular dystrophy
FHL1	Orphanet:97239	Reducing body myopathy
FHL1	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
PRF1	Orphanet:391343	Fatal post-viral neurodegenerative disorder
PRF1	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
PRF1	Orphanet:88	Idiopathic aplastic anemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FHL1	HGNC:3702	ENSG00000022267	Q13642	Four and a half LIM domains protein 1	clinvar
PRF1	HGNC:9360	ENSG00000180644	P14222	Perforin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FHL1	Four and a half LIM domains protein 1	May have an involvement in muscle development or hypertrophy.
PRF1	Perforin-1	Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	134.0×	0.015
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FHL1	Transcription factor	no		Znf_LIM, Fhl1, LIM_FHL1/2/3/5_N
PRF1	Complement	yes		C2_dom, MACPF_CS, MACPF

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
blood	1
granulocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FHL1	291	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii
PRF1	220	broad	marker	granulocyte, blood, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRF1	3,299
FHL1	1,431

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FHL1	Q13642	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRF1	P14222	91.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Nuclear events stimulated by ALK signaling in cancer	1	326.3×	0.003	PRF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of killing of cells of another organism	1	8426.0×	0.003	PRF1
immune response to tumor cell	1	2808.7×	0.004	PRF1
granzyme-mediated programmed cell death signaling pathway	1	1053.2×	0.004	PRF1
regulation of atrial cardiac muscle cell membrane depolarization	1	936.2×	0.004	FHL1
protein import	1	842.6×	0.004	PRF1
immunological synapse formation	1	648.1×	0.004	PRF1
defense response to tumor cell	1	648.1×	0.004	PRF1
protein transmembrane transport	1	648.1×	0.004	PRF1
T cell mediated cytotoxicity	1	561.7×	0.004	PRF1
negative regulation of G2/M transition of mitotic cell cycle	1	561.7×	0.004	FHL1
positive regulation of potassium ion transmembrane transport	1	495.6×	0.005	FHL1
plasma membrane repair	1	290.6×	0.007	PRF1
ceramide biosynthetic process	1	210.7×	0.009	PRF1
negative regulation of G1/S transition of mitotic cell cycle	1	179.3×	0.010	FHL1
cellular defense response	1	159.0×	0.010	PRF1
killing of cells of another organism	1	135.9×	0.011	PRF1
protein secretion	1	131.7×	0.011	PRF1
animal organ morphogenesis	1	95.8×	0.014	FHL1
muscle organ development	1	83.4×	0.015	FHL1
protein maturation	1	81.8×	0.015	PRF1
negative regulation of cell growth	1	72.0×	0.016	FHL1
protein homooligomerization	1	61.1×	0.019	PRF1
defense response to virus	1	34.7×	0.031	PRF1
cell differentiation	1	14.6×	0.068	FHL1
apoptotic process	1	14.3×	0.068	PRF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FHL1	0	0
PRF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRF1	34	Binding:34

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PRF1
E	Difficult family or no structure, no drug	1	FHL1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FHL1	0	—
PRF1	34	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00368355	PHASE2	COMPLETED	T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts
NCT01494103	PHASE1	ACTIVE_NOT_RECRUITING	Administration of Donor T Cells With the Caspase-9 Suicide Gene

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALEMTUZUMAB	4	1
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
RIMIDUCID	2	1