Neutropenia, severe congenital, 8, autosomal dominant

Summary

Neutropenia, severe congenital, 8, autosomal dominant (MONDO:0032899) is a disease caused by SRP54 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SRP54 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		26	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neutropenia, severe congenital, 8, autosomal dominant
Mondo ID	MONDO:0032899
OMIM	618752
Orphanet	675767
DOID	DOID:0112135
UMLS	C5203411
MedGen	1684816
GARD	0016375
Is cancer (heuristic)	no

Also known as: SCN8

Data availability: 13 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › severe congenital neutropenia › neutropenia, severe congenital, 8, autosomal dominant

Related subtypes (7): autosomal dominant severe congenital neutropenia, X-linked severe congenital neutropenia, autosomal recessive severe congenital neutropenia, neutropenia, severe congenital, 9, autosomal dominant, neutropenia, severe congenital, 10, autosomal recessive, neutropenia, severe congenital, 11, autosomal dominant, neutropenia, severe congenital, 12, autosomal recessive

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

13 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 3 pathogenic, 2 benign/likely benign, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
430850	NM_003136.4(SRP54):c.677G>A (p.Gly226Glu)	SRP54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430851	NM_003136.4(SRP54):c.343A>G (p.Thr115Ala)	SRP54	Pathogenic	no assertion criteria provided
430852	NM_003136.4(SRP54):c.343ACA[2] (p.Thr117del)	SRP54	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810689	NM_003136.4(SRP54):c.668C>A (p.Ala223Asp)	SRP54	Pathogenic	no assertion criteria provided
810690	NM_003136.4(SRP54):c.821G>A (p.Gly274Asp)	SRP54	Pathogenic	no assertion criteria provided
3390972	NM_005257.6(GATA6):c.1358C>A (p.Thr453Asn)	GATA6	Likely pathogenic	criteria provided, single submitter
810688	NM_003136.4(SRP54):c.337G>C (p.Gly113Arg)	SRP54	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2511704	NM_003136.4(SRP54):c.1508A>C (p.Asn503Thr)	SRP54	Uncertain significance	criteria provided, single submitter
3391085	NM_003136.4(SRP54):c.549T>A (p.Asn183Lys)	SRP54	Uncertain significance	criteria provided, single submitter
4278305	NM_032357.4(VMA22):c.373T>A (p.Trp125Arg)	VMA22	Uncertain significance	criteria provided, single submitter
1165954	NM_003136.4(SRP54):c.636A>C (p.Ile212=)	SRP54	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1226273	NM_003136.4(SRP54):c.1327+16_1327+32del	SRP54	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3065819	NM_003136.4(SRP54):c.1008T>A (p.Phe336Leu)	SRP54	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 10 · 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
SRP54	Strong	Autosomal dominant	neutropenia, severe congenital, 8, autosomal dominant	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SRP54	Orphanet:675767	Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency
VMA22	Orphanet:468684	CCDC115-CDG
GATA6	Orphanet:2140	Congenital diaphragmatic hernia
GATA6	Orphanet:2255	Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
GATA6	Orphanet:3303	Tetralogy of Fallot
GATA6	Orphanet:334	Hereditary atrial fibrillation
GATA6	Orphanet:665044	Common arterial trunk with aortic dominance
GATA6	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
GATA6	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA6	Orphanet:99103	Atrial septal defect, ostium secundum type

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
SRP54	HGNC:11301	ENSG00000100883	P61011	Signal recognition particle subunit SRP54	gencc,clinvar
VMA22	HGNC:28178	ENSG00000136710	Q96NT0	Vacuolar ATPase assembly protein VMA22	clinvar
GATA6	HGNC:4174	ENSG00000141448	Q92908	Transcription factor GATA-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SRP54	Signal recognition particle subunit SRP54	Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
VMA22	Vacuolar ATPase assembly protein VMA22	Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis.
GATA6	Transcription factor GATA-6	Transcriptional activator.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SRP54	Other/Unknown	no		SRP54_GTPase_dom, AAA+_ATPase, Signal_recog_particle_SRP54_M
VMA22	Other/Unknown	no		Vma22/CCDC115
GATA6	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

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
body of pancreas	1
islet of Langerhans	1
pancreas	1
cardiac muscle of right atrium	1
ileal mucosa	1
kidney epithelium	1
germinal epithelium of ovary	1
jejunal mucosa	1
parietal pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SRP54	296	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
VMA22	258	ubiquitous	marker	kidney epithelium, ileal mucosa, cardiac muscle of right atrium
GATA6	204	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VMA22	1,501
SRP54	299
GATA6	49

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SRP54	P61011	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VMA22	Q96NT0	83.32
GATA6	Q92908	53.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	380.7×	0.023	GATA6
Formation of definitive endoderm	1	237.9×	0.023	GATA6
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.023	GATA6
Cardiogenesis	1	141.0×	0.023	GATA6
Surfactant metabolism	1	122.8×	0.023	GATA6
SRP-dependent cotranslational protein targeting to membrane	1	33.4×	0.069	SRP54
RHOA GTPase cycle	1	24.9×	0.069	VMA22
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.069	GATA6
Translation	1	20.7×	0.069	SRP54
RHO GTPase cycle	1	20.0×	0.069	VMA22
Signaling by Rho GTPases	1	11.4×	0.101	VMA22
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.101	VMA22
Metabolism of proteins	1	4.1×	0.241	SRP54
Signal Transduction	1	3.4×	0.267	VMA22

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
negative regulation of transforming growth factor beta2 production	1	5617.3×	0.003	GATA6
tube morphogenesis	1	5617.3×	0.003	GATA6
negative regulation of sebum secreting cell proliferation	1	5617.3×	0.003	GATA6
regulation of antimicrobial humoral response	1	2808.7×	0.003	GATA6
endodermal cell fate determination	1	2808.7×	0.003	GATA6
sebaceous gland cell differentiation	1	1872.4×	0.003	GATA6
positive regulation of cardiac muscle myoblast proliferation	1	1872.4×	0.003	GATA6
SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition	1	1404.3×	0.003	SRP54
cardiac vascular smooth muscle cell differentiation	1	1404.3×	0.003	GATA6
skin epidermis development	1	1404.3×	0.003	GATA6
animal organ formation	1	1123.5×	0.003	GATA6
club cell differentiation	1	1123.5×	0.003	GATA6
atrioventricular node development	1	936.2×	0.003	GATA6
negative regulation of transforming growth factor beta1 production	1	936.2×	0.003	GATA6
vacuolar proton-transporting V-type ATPase complex assembly	1	936.2×	0.003	VMA22
G1 to G0 transition involved in cell differentiation	1	936.2×	0.003	GATA6
cellular response to gonadotropin stimulus	1	936.2×	0.003	GATA6
pancreatic A cell differentiation	1	802.5×	0.003	GATA6
sinoatrial node development	1	702.2×	0.003	GATA6
type B pancreatic cell differentiation	1	702.2×	0.003	GATA6
SRP-dependent cotranslational protein targeting to membrane	1	702.2×	0.003	SRP54
SRP-dependent cotranslational protein targeting to membrane, translocation	1	702.2×	0.003	SRP54
cellular response to increased oxygen levels	1	702.2×	0.003	VMA22
lung saccule development	1	702.2×	0.003	GATA6
type II pneumocyte differentiation	1	702.2×	0.003	GATA6
exocrine pancreas development	1	561.7×	0.004	SRP54
atrioventricular canal development	1	510.7×	0.004	GATA6
intestinal epithelial cell differentiation	1	510.7×	0.004	GATA6
response to growth factor	1	468.1×	0.004	GATA6
granulocyte differentiation	1	401.2×	0.005	SRP54

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRP54	0	0
VMA22	0	0
GATA6	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
SRP54	2	Binding:2

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

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	3	SRP54, VMA22, GATA6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SRP54	2	—
VMA22	0	—
GATA6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.