Congenital neutropenia-myelofibrosis-nephromegaly syndrome

Summary

Congenital neutropenia-myelofibrosis-nephromegaly syndrome (MONDO:0014118) is a disease caused by VPS45 (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VPS45 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 611

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital neutropenia-myelofibrosis-nephromegaly syndrome
Mondo ID	MONDO:0014118
OMIM	615285
Orphanet	369852
DOID	DOID:0112132
UMLS	C3809031
MedGen	815361
GARD	0017585
Is cancer (heuristic)	no

Also known as: congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome · neutropenia, severe congenital, 5, autosomal recessive · SCN5 · vps45 deficiency

Data availability: 611 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive severe congenital neutropenia › congenital neutropenia-myelofibrosis-nephromegaly syndrome

Related subtypes (5): Kostmann syndrome, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, autosomal recessive severe congenital neutropenia due to JAGN1 deficiency, autosomal recessive severe congenital neutropenia due to CSF3R deficiency, autosomal recessive severe congenital neutropenia due to CXCR2 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

600 retrieved; paginated sample, class counts are floors:

395 likely benign, 160 uncertain significance, 14 conflicting classifications of pathogenicity, 14 likely pathogenic, 9 benign, 7 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
55906	NM_007259.5(VPS45):c.671C>A (p.Thr224Asn)	VPS45	Pathogenic	criteria provided, multiple submitters, no conflicts
4063279	NM_007259.5(VPS45):c.30C>G (p.Tyr10Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4063281	NM_007259.5(VPS45):c.702del (p.Met235fs)	VPS45	Likely pathogenic	criteria provided, single submitter
4063282	NM_007259.5(VPS45):c.1420del (p.Leu474fs)	VPS45	Likely pathogenic	criteria provided, single submitter
4815523	NM_007259.5(VPS45):c.1173T>G (p.Tyr391Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815524	NM_007259.5(VPS45):c.1257T>G (p.Tyr419Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815525	NM_007259.5(VPS45):c.1258C>T (p.Arg420Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815526	NM_007259.5(VPS45):c.1297C>T (p.Arg433Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815527	NM_007259.5(VPS45):c.178C>T (p.Arg60Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815528	NM_007259.5(VPS45):c.272del (p.Tyr91fs)	VPS45	Likely pathogenic	criteria provided, single submitter
4815529	NM_007259.5(VPS45):c.387C>G (p.Tyr129Ter)	VPS45	Likely pathogenic	criteria provided, single submitter
4815530	NM_007259.5(VPS45):c.390_403delinsG (p.Ile130fs)	VPS45	Likely pathogenic	criteria provided, single submitter
4815531	NM_007259.5(VPS45):c.769_770insTG (p.Lys257fs)	VPS45	Likely pathogenic	criteria provided, single submitter
4815533	NM_007259.5(VPS45):c.896del (p.Pro299fs)	VPS45	Likely pathogenic	criteria provided, single submitter
55907	NM_007259.5(VPS45):c.712G>A (p.Glu238Lys)	VPS45	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1025100	NM_007259.5(VPS45):c.652C>T (p.Arg218Cys)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040041	NM_007259.5(VPS45):c.1157G>A (p.Arg386His)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1149442	NM_007259.5(VPS45):c.1255T>C (p.Tyr419His)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336803	NM_007259.5(VPS45):c.888G>A (p.Lys296=)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2202548	NM_007259.5(VPS45):c.1226_1227insATTCCTGAGGAACA (p.Asp409fs)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541272	NM_007259.5(VPS45):c.1442G>A (p.Arg481Lys)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713883	NM_007259.5(VPS45):c.625G>T (p.Val209Phe)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715350	NM_007259.5(VPS45):c.1556A>G (p.Tyr519Cys)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733547	NM_007259.5(VPS45):c.1197C>A (p.Ser399Arg)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
791006	NM_007259.5(VPS45):c.758C>T (p.Pro253Leu)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
793965	NM_007259.5(VPS45):c.369+8T>A	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
835122	NM_007259.5(VPS45):c.1018C>T (p.Arg340Ter)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863222	NM_007259.5(VPS45):c.442C>T (p.Arg148Ter)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
864158	NM_007259.5(VPS45):c.695_696del (p.Tyr232fs)	VPS45	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1411622	NC_000001.10:g.(?150044213)(150477474_?)dup	ANP32E	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
VPS45	Strong	Autosomal recessive	congenital neutropenia-myelofibrosis-nephromegaly syndrome	3
RBSN	Supportive	Autosomal recessive	congenital neutropenia-myelofibrosis-nephromegaly syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS45	Orphanet:369852	Congenital neutropenia-myelofibrosis-nephromegaly syndrome
RBSN	Orphanet:675775	Severe congenital myelofibrosis-pancytopenia-intellectual disability-neurologic and ophthalmic abnormalities syndrome
RBSN	Orphanet:675782	Progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN
ECM1	Orphanet:530	Lipoid proteinosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS45	HGNC:14579	ENSG00000136631	Q9NRW7	Vacuolar protein sorting-associated protein 45	gencc,clinvar
RBSN	HGNC:20759	ENSG00000131381	Q9H1K0	Rabenosyn-5	gencc
ANP32E	HGNC:16673	ENSG00000143401	Q9BTT0	Acidic leucine-rich nuclear phosphoprotein 32 family member E	clinvar
ECM1	HGNC:3153	ENSG00000143369	Q16610	Extracellular matrix protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS45	Vacuolar protein sorting-associated protein 45	May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network.
RBSN	Rabenosyn-5	Rab4/Rab5 effector protein acting in early endocytic membrane fusion and membrane trafficking of recycling endosomes.
ANP32E	Acidic leucine-rich nuclear phosphoprotein 32 family member E	Histone chaperone that specifically mediates the genome-wide removal of histone H2A.Z/H2AZ1 from the nucleosome: removes H2A.Z/H2AZ1 from its normal sites of deposition, especially from enhancer and insulator regions.
ECM1	Extracellular matrix protein 1	Involved in endochondral bone formation as negative regulator of bone mineralization.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

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
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS45	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
RBSN	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
ANP32E	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, AN32
ECM1	Other/Unknown	no		ECM1, Serum_albumin-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cardiac muscle of right atrium	1
endothelial cell	1
left ventricle myocardium	1
caput epididymis	1
corpus epididymis	1
trabecular bone tissue	1
buccal mucosa cell	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS45	291	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
RBSN	255	ubiquitous	marker	endothelial cell, left ventricle myocardium, cardiac muscle of right atrium
ANP32E	291	ubiquitous	marker	trabecular bone tissue, caput epididymis, corpus epididymis
ECM1	253	ubiquitous	marker	lower esophagus mucosa, buccal mucosa cell, pharyngeal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ECM1	1,835
VPS45	1,764
RBSN	1,505
ANP32E	1,366

Intra-cohort edges

A	B	Sources
RBSN	VPS45	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBSN	Q9H1K0	3
ANP32E	Q9BTT0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS45	Q9NRW7	90.65
ECM1	Q16610	69.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 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
Factors involved in megakaryocyte development and platelet production	2	44.3×	0.003	VPS45, RBSN
SARS-CoV-2 modulates autophagy	1	346.1×	0.007	VPS45
Intra-Golgi traffic	1	86.5×	0.019	VPS45
Toll Like Receptor 9 (TLR9) Cascade	1	58.6×	0.021	RBSN
Platelet degranulation	1	29.3×	0.034	ECM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of type 2 immune response	1	4213.0×	0.006	ECM1
negative regulation of peptidase activity	1	2106.5×	0.006	ECM1
regulation of T cell migration	1	601.9×	0.011	ECM1
negative regulation of cytokine-mediated signaling pathway	1	468.1×	0.011	ECM1
endochondral bone growth	1	421.3×	0.011	ECM1
Golgi to lysosome transport	1	383.0×	0.011	RBSN
early endosome to Golgi transport	1	324.1×	0.011	RBSN
regulation of Golgi organization	1	280.9×	0.011	RBSN
chondrocyte development	1	234.1×	0.011	ECM1
negative regulation of bone mineralization	1	234.1×	0.011	ECM1
regulation of bone mineralization	1	183.2×	0.013	ECM1
biomineral tissue development	1	162.0×	0.013	ECM1
endosomal transport	1	61.1×	0.030	RBSN
positive regulation of endothelial cell proliferation	1	57.7×	0.030	ECM1
ossification	1	56.9×	0.030	ECM1
positive regulation of angiogenesis	1	28.9×	0.056	ECM1
chromatin organization	1	24.8×	0.059	ANP32E
vesicle-mediated transport	1	24.1×	0.059	VPS45
regulation of apoptotic process	1	20.9×	0.064	ANP32E
positive regulation of canonical NF-kappaB signal transduction	1	18.2×	0.070	ECM1
intracellular protein transport	1	16.2×	0.074	VPS45
angiogenesis	1	15.6×	0.074	ECM1
protein transport	1	11.0×	0.100	RBSN
inflammatory response	1	9.4×	0.110	ECM1
signal transduction	1	4.0×	0.236	ECM1
regulation of transcription by RNA polymerase II	1	2.9×	0.302	ECM1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS45	0	0
RBSN	0	0
ANP32E	0	0
ECM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
E	Difficult family or no structure, no drug	4	VPS45, RBSN, ANP32E, ECM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS45	0	—
RBSN	0	—
ANP32E	0	—
ECM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.