Kostmann syndrome

Summary

Kostmann syndrome (MONDO:0012548) is a disease caused by HAX1 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HAX1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 431
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		45	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Annual incidence	<1 / 1 000 000	0.0425	Brazil	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Kostmann syndrome
Mondo ID	MONDO:0012548
MeSH	C537592
OMIM	610738
Orphanet	99749
DOID	DOID:0112133
ICD-11	421553273
NCIT	C166153
UMLS	C5235141
MedGen	1713491
GARD	0000302
Is cancer (heuristic)	no

Also known as: agranulocytosis infantile · infantile agranulocytosis · neutropenia, severe congenital 3, autosomal recessive · neutropenia, severe congenital, 3, autosomal recessive · SCN3 · severe congenital neutropenia autosomal recessive 3 · severe congenital neutropenia type 3

Data availability: 431 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › Kostmann syndrome

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

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

431 retrieved; paginated sample, class counts are floors:

209 likely benign, 135 uncertain significance, 33 pathogenic, 25 likely pathogenic, 12 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 6 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068848	NM_006118.4(HAX1):c.235_236del (p.Phe79fs)	HAX1	Pathogenic	criteria provided, single submitter
1071627	NM_006118.4(HAX1):c.146del (p.Pro49fs)	HAX1	Pathogenic	criteria provided, single submitter
1072845	NM_006118.4(HAX1):c.349G>T (p.Glu117Ter)	HAX1	Pathogenic	criteria provided, single submitter
1339545	NM_006118.4(HAX1):c.372_373insGATA (p.Leu125fs)	HAX1	Pathogenic	criteria provided, single submitter
1366366	NM_006118.4(HAX1):c.480G>A (p.Trp160Ter)	HAX1	Pathogenic	criteria provided, single submitter
1374231	NM_006118.4(HAX1):c.214_217dup (p.Ile73fs)	HAX1	Pathogenic	criteria provided, single submitter
1395898	NM_006118.4(HAX1):c.487C>T (p.Gln163Ter)	HAX1	Pathogenic	criteria provided, single submitter
1410664	NM_006118.4(HAX1):c.166del (p.His56fs)	HAX1	Pathogenic	criteria provided, single submitter
1438742	NM_006118.4(HAX1):c.368_381del (p.Gln123fs)	HAX1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453309	NM_006118.4(HAX1):c.556+1del	HAX1	Pathogenic	criteria provided, single submitter
1453573	NM_006118.4(HAX1):c.58dup (p.Arg20fs)	HAX1	Pathogenic	criteria provided, single submitter
1492255	NM_006118.4(HAX1):c.557-1G>C	HAX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2033309	NM_006118.4(HAX1):c.518G>A (p.Trp173Ter)	HAX1	Pathogenic	criteria provided, single submitter
2098070	NM_006118.4(HAX1):c.216_217insC (p.Ile73fs)	HAX1	Pathogenic	criteria provided, single submitter
2116504	NM_006118.4(HAX1):c.154_155dup (p.Ser53fs)	HAX1	Pathogenic	criteria provided, single submitter
2415426	NM_006118.4(HAX1):c.163C>T (p.Gln55Ter)	HAX1	Pathogenic	criteria provided, single submitter
2632756	NM_006118.4(HAX1):c.109G>T (p.Glu37Ter)	HAX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2715418	NM_006118.4(HAX1):c.43G>T (p.Gly15Ter)	HAX1	Pathogenic	criteria provided, single submitter
2806834	NM_006118.4(HAX1):c.432del (p.Leu145fs)	HAX1	Pathogenic	criteria provided, single submitter
2821680	NM_006118.4(HAX1):c.314dup (p.Pro105_Glu106insTer)	HAX1	Pathogenic	criteria provided, single submitter
2858293	NM_006118.4(HAX1):c.16del (p.Leu6fs)	HAX1	Pathogenic	criteria provided, single submitter
2858843	NM_006118.4(HAX1):c.103_106del (p.Glu35fs)	HAX1	Pathogenic	criteria provided, single submitter
2907291	NM_006118.4(HAX1):c.505-1G>C	HAX1	Pathogenic	criteria provided, single submitter
2911290	NM_006118.4(HAX1):c.173del (p.Pro58fs)	HAX1	Pathogenic	criteria provided, single submitter
2981323	NM_006118.4(HAX1):c.85C>T (p.Arg29Ter)	HAX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3002493	NM_006118.4(HAX1):c.11_12del (p.Leu3_Phe4insTer)	HAX1	Pathogenic	criteria provided, single submitter
3713886	NM_006118.4(HAX1):c.339_340del (p.Glu113fs)	HAX1	Pathogenic	criteria provided, single submitter
419887	NM_006118.4(HAX1):c.91del (p.Glu31fs)	HAX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4650	NM_006118.4(HAX1):c.568C>T (p.Gln190Ter)	HAX1	Pathogenic	no assertion criteria provided
4651	NM_006118.4(HAX1):c.130_131insA (p.Trp44Ter)	HAX1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
HAX1	Definitive	Autosomal recessive	Kostmann syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HAX1	Orphanet:99749	Kostmann syndrome
ECM1	Orphanet:530	Lipoid proteinosis

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
HAX1	HGNC:16915	ENSG00000143575	O00165	HCLS1-associated protein X-1	gencc,clinvar
TDRD10	HGNC:25316	ENSG00000163239	Q5VZ19	Tudor domain-containing protein 10	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)
HAX1	HCLS1-associated protein X-1	Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex.
ECM1	Extracellular matrix protein 1	Involved in endochondral bone formation as negative regulator of bone mineralization.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HAX1	Other/Unknown	no		HAX-1
TDRD10	Other/Unknown	no		RRM_dom, Tudor, Nucleotide-bd_a/b_plait_sf
ECM1	Other/Unknown	no		ECM1, Serum_albumin-like

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart right ventricle	1
hindlimb stylopod muscle	1
left testis	1
right testis	1
sperm	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
HAX1	295	ubiquitous	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle
TDRD10	177	tissue_specific	yes	left testis, right testis, sperm
ECM1	253	ubiquitous	marker	lower esophagus mucosa, buccal mucosa cell, pharyngeal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HAX1	2,243
ECM1	1,835
TDRD10	307

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TDRD10	Q5VZ19	72.71
ECM1	Q16610	69.05
HAX1	O00165	60.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Platelet degranulation	1	87.8×	0.011	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 2 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	8426.0×	0.003	ECM1
negative regulation of peptidase activity	1	4213.0×	0.003	ECM1
granulocyte colony-stimulating factor signaling pathway	1	1685.2×	0.003	HAX1
positive regulation of granulocyte differentiation	1	1404.3×	0.003	HAX1
regulation of autophagy of mitochondrion	1	1404.3×	0.003	HAX1
regulation of actin filament organization	1	1203.7×	0.003	HAX1
regulation of T cell migration	1	1203.7×	0.003	ECM1
obsolete regulation of protein targeting to mitochondrion	1	1053.2×	0.003	HAX1
negative regulation of cytokine-mediated signaling pathway	1	936.2×	0.003	ECM1
endochondral bone growth	1	842.6×	0.003	ECM1
chondrocyte development	1	468.1×	0.005	ECM1
negative regulation of bone mineralization	1	468.1×	0.005	ECM1
regulation of bone mineralization	1	366.4×	0.006	ECM1
biomineral tissue development	1	324.1×	0.006	ECM1
regulation of actin filament polymerization	1	290.6×	0.006	HAX1
cellular response to cytokine stimulus	1	271.8×	0.006	HAX1
positive regulation of endothelial cell proliferation	1	115.4×	0.014	ECM1
ossification	1	113.9×	0.014	ECM1
positive regulation of angiogenesis	1	57.7×	0.025	ECM1
regulation of apoptotic process	1	41.7×	0.033	HAX1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.034	HAX1
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.035	ECM1
angiogenesis	1	31.2×	0.039	ECM1
inflammatory response	1	18.9×	0.061	ECM1
negative regulation of apoptotic process	1	17.4×	0.064	HAX1
signal transduction	1	8.0×	0.130	ECM1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.135	HAX1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ECM1

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
HAX1	0	0
TDRD10	0	0
ECM1	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
HAX1	3	Binding:3

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	HAX1, TDRD10, ECM1

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)
HAX1	3	—
TDRD10	0	—
ECM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00244010	Not specified	COMPLETED	Partially Matched Stem Cell Transplantation for Patients With Refractory Severe Aplastic Anemia or Refractory Cytopenias