Cyclic hematopoiesis

Summary

Cyclic hematopoiesis (MONDO:0008090) is a disease caused by ELANE (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: ELANE (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 520
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000246	Sinusitis	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0040289	Cyclic neutropenia	Very frequent (80-99%)
HP:0000155	Oral ulcer	Frequent (30-79%)
HP:0000230	Gingivitis	Frequent (30-79%)
HP:0001581	Recurrent skin infections	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0011110	Recurrent tonsillitis	Frequent (30-79%)
HP:0011947	Respiratory tract infection	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0025289	Cervical lymphadenopathy	Frequent (30-79%)
HP:0025439	Pharyngitis	Frequent (30-79%)
HP:0030757	Tooth abscess	Frequent (30-79%)
HP:0032323	Periodic fever	Frequent (30-79%)
HP:0000388	Otitis media	Occasional (5-29%)
HP:0000704	Periodontitis	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001888	Lymphopenia	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0006308	Atrophy of alveolar ridges	Occasional (5-29%)
HP:0006357	Premature loss of permanent teeth	Occasional (5-29%)
HP:0009789	Perianal abscess	Occasional (5-29%)
HP:0031690	Opportunistic infection	Occasional (5-29%)
HP:0031891	Decreased eosinophil count	Occasional (5-29%)
HP:0100658	Cellulitis	Occasional (5-29%)
HP:0002586	Peritonitis	Very rare (<1-4%)
HP:0004387	Enterocolitis	Very rare (<1-4%)
HP:0031864	Bacteremia	Very rare (<1-4%)
HP:0032169	Severe infection	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cyclic hematopoiesis
Mondo ID	MONDO:0008090
MeSH	C536227
OMIM	162800
Orphanet	2686
DOID	DOID:5339
ICD-10-CM	D70.4
NCIT	C3820
SNOMED CT	191347008
UMLS	C0221023
MedGen	65121
GARD	0006229
MedDRA	10053176
Is cancer (heuristic)	no

Also known as: CH · CN · cyclic agranulocytosis · cyclic hematopoiesis · dysplasia, myelocytic periodic · neutropenia cyclic · neutropenia, cyclic · periodic neutropenia

Data availability: 520 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › agranulocytosis › neutropenia › constitutional neutropenia › cyclic hematopoiesis

Related subtypes (12): Chediak-Higashi syndrome, Cohen syndrome, glycogen storage disease Ib, Lichtenstein syndrome, Barth syndrome, poikiloderma with neutropenia, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, primary immunodeficiency syndrome due to p14 deficiency, neutropenia-monocytopenia-deafness syndrome, severe congenital neutropenia, WHIM syndrome 1

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

520 retrieved; paginated sample, class counts are floors:

243 uncertain significance, 140 likely benign, 55 conflicting classifications of pathogenicity, 31 pathogenic, 21 benign/likely benign, 17 likely pathogenic, 7 pathogenic/likely pathogenic, 5 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
16745	NM_001972.4(ELANE):c.377C>T (p.Ser126Leu)	CFD	Pathogenic	criteria provided, multiple submitters, no conflicts
939547	NM_001972.4(ELANE):c.607G>C (p.Gly203Arg)	CFD	Pathogenic	criteria provided, multiple submitters, no conflicts
1052483	NM_001972.4(ELANE):c.723G>A (p.Trp241Ter)	ELANE	Pathogenic	criteria provided, single submitter
1069597	NM_001972.4(ELANE):c.597+5G>T	ELANE	Pathogenic	criteria provided, single submitter
1069598	NM_001972.4(ELANE):c.687del (p.Asp230fs)	ELANE	Pathogenic	criteria provided, single submitter
1343367	NM_001972.4(ELANE):c.1A>G (p.Met1Val)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
1343817	NM_001972.4(ELANE):c.242G>C (p.Arg81Pro)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372707	NM_001972.4(ELANE):c.461T>G (p.Met154Arg)	ELANE	Pathogenic	criteria provided, single submitter
1402531	NM_001972.4(ELANE):c.367-8C>A	ELANE	Pathogenic	criteria provided, single submitter
1495615	NM_001972.4(ELANE):c.169G>A (p.Ala57Thr)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
16738	NM_001972.4(ELANE):c.659G>A (p.Arg220Gln)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16740	NM_001972.4(ELANE):c.182C>T (p.Ala61Val)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16743	NM_001972.4(ELANE):c.416C>T (p.Pro139Leu)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16746	NM_001972.4(ELANE):c.211T>C (p.Cys71Arg)	ELANE	Pathogenic	no assertion criteria provided
16748	NM_001972.4(ELANE):c.640G>A (p.Gly214Arg)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
1918199	NM_001972.4(ELANE):c.538del (p.Leu180fs)	ELANE	Pathogenic	criteria provided, single submitter
208494	NM_001972.4(ELANE):c.561C>A (p.Cys187Ter)	ELANE	Pathogenic	criteria provided, single submitter
2138169	NM_001972.4(ELANE):c.197T>G (p.Met66Arg)	ELANE	Pathogenic	criteria provided, single submitter
2138170	NM_001972.4(ELANE):c.416C>G (p.Pro139Arg)	ELANE	Pathogenic	criteria provided, single submitter
242287	NM_001972.4(ELANE):c.597+1G>A	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
242289	NM_001972.4(ELANE):c.140T>C (p.Leu47Pro)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
245598	NM_001972.4(ELANE):c.597+5G>A	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
245599	NM_001972.4(ELANE):c.597+1G>C	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
2925630	NM_001972.4(ELANE):c.164G>A (p.Cys55Tyr)	ELANE	Pathogenic	criteria provided, single submitter
2942789	NM_001972.4(ELANE):c.639del (p.His213fs)	ELANE	Pathogenic	criteria provided, single submitter
2947200	NM_001972.4(ELANE):c.129C>G (p.Phe43Leu)	ELANE	Pathogenic	criteria provided, single submitter
372362	NM_001972.4(ELANE):c.137C>T (p.Ser46Phe)	ELANE	Pathogenic	criteria provided, multiple submitters, no conflicts
3759509	NM_001972.4(ELANE):c.597+1G>T	ELANE	Pathogenic	criteria provided, single submitter
3778313	NM_001972.4(ELANE):c.3G>A (p.Met1Ile)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418179	NM_001972.4(ELANE):c.251T>C (p.Leu84Pro)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ELANE	Strong	Autosomal dominant	cyclic hematopoiesis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia
CFD	Orphanet:169467	Recurrent Neisseria infections due to factor D deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	gencc,clinvar
CFD	HGNC:2771	ENSG00000197766	P00746	Complement factor D	clinvar
ABCA7	HGNC:37	ENSG00000064687	Q8IZY2	Phospholipid-transporting ATPase ABCA7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELANE	Neutrophil elastase	Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes.
CFD	Complement factor D	Serine protease that initiates the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.
ABCA7	Phospholipid-transporting ATPase ABCA7	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	2	24.4×	0.004
Transporter	1	25.9×	0.038

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
CFD	Protease	yes	3.4.21.46	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
ABCA7	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
monocyte	1
adipose tissue	1
mucosa of stomach	1
subcutaneous adipose tissue	1
adenohypophysis	1
granulocyte	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELANE	124	tissue_specific	marker	bone marrow, bone marrow cell, monocyte
CFD	133	broad	marker	subcutaneous adipose tissue, adipose tissue, mucosa of stomach
ABCA7	231	ubiquitous	marker	granulocyte, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELANE	2,758
CFD	1,604
ABCA7	1,520

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFD	P00746	40
ELANE	P08246	38
ABCA7	Q8IZY2	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative complement activation	1	761.3×	0.009	CFD
Expression of NOTCH2NL genes	1	761.3×	0.009	ELANE
ABC transporters in lipid homeostasis	1	200.3×	0.018	ABCA7
Neutrophil degranulation	2	15.4×	0.018	ELANE, CFD
Pyroptosis	1	141.0×	0.018	ELANE
Activation of Matrix Metalloproteinases	1	102.9×	0.021	ELANE
Regulation of Complement cascade	1	77.7×	0.022	ELANE
Antimicrobial peptides	1	74.6×	0.022	ELANE
Collagen degradation	1	58.6×	0.025	ELANE
ABC-family protein mediated transport	1	40.5×	0.030	ABCA7
Degradation of the extracellular matrix	1	39.2×	0.030	ELANE
Platelet degranulation	1	29.3×	0.037	CFD
Transport of small molecules	1	8.4×	0.115	ABCA7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phagocytosis	2	160.5×	0.003	ELANE, ABCA7
biosynthetic process of antibacterial peptides active against Gram-negative bacteria	1	5617.3×	0.005	ELANE
neutrophil-mediated killing of fungus	1	2808.7×	0.005	ELANE
positive regulation of engulfment of apoptotic cell	1	2808.7×	0.005	ABCA7
negative regulation of chemotaxis	1	1872.4×	0.005	ELANE
apolipoprotein A-I-mediated signaling pathway	1	1404.3×	0.005	ABCA7
positive regulation of phospholipid efflux	1	1404.3×	0.005	ABCA7
neutrophil-mediated killing of gram-negative bacterium	1	1123.5×	0.005	ELANE
regulation of amyloid precursor protein catabolic process	1	1123.5×	0.005	ABCA7
acute inflammatory response to antigenic stimulus	1	936.2×	0.005	ELANE
plasma membrane raft organization	1	936.2×	0.005	ABCA7
response to yeast	1	702.2×	0.005	ELANE
negative regulation of chemokine production	1	702.2×	0.005	ELANE
negative regulation of amyloid precursor protein biosynthetic process	1	702.2×	0.005	ABCA7
amyloid-beta clearance by cellular catabolic process	1	702.2×	0.005	ABCA7
positive regulation of amyloid-beta clearance	1	702.2×	0.005	ABCA7
amyloid-beta formation	1	624.1×	0.005	ABCA7
high-density lipoprotein particle assembly	1	561.7×	0.005	ABCA7
positive regulation of leukocyte tethering or rolling	1	510.7×	0.006	ELANE
negative regulation of PERK-mediated unfolded protein response	1	468.1×	0.006	ABCA7
leukocyte migration involved in inflammatory response	1	401.2×	0.006	ELANE
proteolysis	2	22.8×	0.006	ELANE, CFD
phospholipid efflux	1	374.5×	0.006	ABCA7
complement activation, alternative pathway	1	330.4×	0.007	CFD
negative regulation of interleukin-8 production	1	330.4×	0.007	ELANE
negative regulation of endocytosis	1	312.1×	0.007	ABCA7
negative regulation of amyloid-beta formation	1	295.6×	0.007	ABCA7
positive regulation of protein localization to cell surface	1	255.3×	0.008	ABCA7
zymogen activation	1	224.7×	0.008	CFD
positive regulation of MAP kinase activity	1	216.1×	0.008	ELANE

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ELANE	BOCEPREVIR
CFD	DANICOPAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ELANE	11	4
CFD	1	4
ABCA7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
DANICOPAN	4	CFD
EPIGALOCATECHIN GALLATE	3	ELANE
QUERCETIN	3	ELANE
SIVELESTAT	3	ELANE
LUTEOLIN	2	ELANE
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
CFD	82	Binding:81, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ELANE	3.4.21.37	leukocyte elastase
CFD	3.4.21.46	complement factor D

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ELANE	801

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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.

Compound	Max phase	Cohort target (bioactivity)
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
DANICOPAN	4	CFD
EPIGALOCATECHIN GALLATE	3	ELANE
QUERCETIN	3	ELANE
SIVELESTAT	3	ELANE
LUTEOLIN	2	ELANE
MIDESTEINE	2	ELANE
FRESELESTAT	2	ELANE
DELANZOMIB	2	ELANE
ALVELESTAT	2	ELANE

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ELANE, CFD
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCA7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ABCA7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.