Autosomal dominant severe congenital neutropenia

Summary

Autosomal dominant severe congenital neutropenia (MONDO:0008742) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Cohort genes: 4
• ClinVar variants: 1
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001875	Decreased total neutrophil count	Obligate (100%)
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0004429	Recurrent viral infections	Very frequent (80-99%)
HP:0000155	Oral ulcer	Frequent (30-79%)
HP:0000230	Gingivitis	Frequent (30-79%)
HP:0000704	Periodontitis	Frequent (30-79%)
HP:0001581	Recurrent skin infections	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002090	Pneumonia	Frequent (30-79%)
HP:0004798	Recurrent infection of the gastrointestinal tract	Frequent (30-79%)
HP:0005425	Recurrent sinopulmonary infections	Frequent (30-79%)
HP:0011107	Recurrent aphthous stomatitis	Frequent (30-79%)
HP:0012311	Monocytosis	Frequent (30-79%)
HP:0012384	Rhinitis	Frequent (30-79%)
HP:0025439	Pharyngitis	Frequent (30-79%)
HP:0410018	Recurrent ear infections	Frequent (30-79%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0001028	Hemangioma	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0001909	Leukemia	Occasional (5-29%)
HP:0001915	Aplastic anemia	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0003453	Antineutrophil antibody positivity	Occasional (5-29%)
HP:0004808	Acute myeloid leukemia	Occasional (5-29%)
HP:0006480	Premature loss of teeth	Occasional (5-29%)
HP:0006721	Acute lymphoblastic leukemia	Occasional (5-29%)
HP:0025452	Pyoderma gangrenosum	Occasional (5-29%)
HP:0100658	Cellulitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant severe congenital neutropenia
Mondo ID	MONDO:0008742
Orphanet	486
DOID	DOID:0112130
NCIT	C166155
UMLS	C4749612
MedGen	1665322
GARD	0009558
Is cancer (heuristic)	no

Also known as: severe congenital neutropenia autosomal dominant · severe congenital neutropenia, autosomal dominant

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (3): neutropenia, lethal congenital, with eosinophilia, neutropenia, severe congenital, 2, autosomal dominant, neutropenia, severe congenital, 1, autosomal dominant

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

1 retrieved; paginated sample, class counts are floors:

1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3366285	NM_001972.4(ELANE):c.674C>G (p.Ser225Ter)	ELANE	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 8 · 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	Definitive	Autosomal dominant	neutropenia	5
GFI1	Strong	Autosomal dominant	neutropenia, severe congenital, 2, autosomal dominant	5
SRP54	Strong	Autosomal dominant	neutropenia, severe congenital, 8, autosomal dominant	5
TCIRG1	Supportive	Autosomal dominant	autosomal dominant severe congenital neutropenia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia
SRP54	Orphanet:675767	Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
GFI1	Orphanet:486	Autosomal dominant severe congenital neutropenia

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
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	gencc,clinvar
SRP54	HGNC:11301	ENSG00000100883	P61011	Signal recognition particle subunit SRP54	gencc
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	gencc
GFI1	HGNC:4237	ENSG00000162676	Q99684	Zinc finger protein Gfi-1	gencc

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.
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).
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
GFI1	Zinc finger protein Gfi-1	Transcription repressor essential for hematopoiesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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	1	9.2×	0.315
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
SRP54	Other/Unknown	no		SRP54_GTPase_dom, AAA+_ATPase, Signal_recog_particle_SRP54_M
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
GFI1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	2
bone marrow cell	2
granulocyte	2
monocyte	1
body of pancreas	1
islet of Langerhans	1
pancreas	1
blood	1
spleen	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
SRP54	296	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
GFI1	153	broad	yes	granulocyte, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELANE	2,758
GFI1	2,148
TCIRG1	1,931
SRP54	299

Intra-cohort edges

A	B	Sources
ELANE	GFI1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ELANE	P08246	38
SRP54	P61011	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52
GFI1	Q99684	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Expression of NOTCH2NL genes	1	571.0×	0.030	ELANE
Pyroptosis	1	105.7×	0.031	ELANE
Insulin receptor recycling	1	95.2×	0.031	TCIRG1
Transferrin endocytosis and recycling	1	92.1×	0.031	TCIRG1
ROS and RNS production in phagocytes	1	84.0×	0.031	TCIRG1
Activation of Matrix Metalloproteinases	1	77.2×	0.031	ELANE
Neutrophil degranulation	2	11.5×	0.031	ELANE, TCIRG1
Regulation of Complement cascade	1	58.3×	0.034	ELANE
Antimicrobial peptides	1	56.0×	0.034	ELANE
Amino acids regulate mTORC1	1	50.1×	0.034	TCIRG1
Collagen degradation	1	43.9×	0.035	ELANE
Transcriptional regulation of granulopoiesis	1	31.4×	0.044	GFI1
Degradation of the extracellular matrix	1	29.4×	0.044	ELANE
SRP-dependent cotranslational protein targeting to membrane	1	25.0×	0.047	SRP54
Ion channel transport	1	24.0×	0.047	TCIRG1
Translation	1	15.5×	0.067	SRP54
Metabolism of proteins	1	3.1×	0.286	SRP54

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
biosynthetic process of antibacterial peptides active against Gram-negative bacteria	1	4213.0×	0.005	ELANE
response to silver ion	1	4213.0×	0.005	TCIRG1
dentin mineralization	1	4213.0×	0.005	TCIRG1
protein catabolic process in the vacuole	1	2106.5×	0.005	TCIRG1
memory T cell activation	1	2106.5×	0.005	TCIRG1
neutrophil-mediated killing of fungus	1	2106.5×	0.005	ELANE
regulation of proton transport	1	1404.3×	0.005	TCIRG1
T-helper 1 cell activation	1	1404.3×	0.005	TCIRG1
negative regulation of chemotaxis	1	1404.3×	0.005	ELANE
positive regulation of interleukin-6-mediated signaling pathway	1	1404.3×	0.005	GFI1
intracellular calcium ion homeostasis	2	72.6×	0.005	ELANE, TCIRG1
SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition	1	1053.2×	0.006	SRP54
negative regulation of vitamin D biosynthetic process	1	1053.2×	0.006	GFI1
osteoclast proliferation	1	842.6×	0.006	TCIRG1
tooth eruption	1	842.6×	0.006	TCIRG1
neutrophil-mediated killing of gram-negative bacterium	1	842.6×	0.006	ELANE
acute inflammatory response to antigenic stimulus	1	702.2×	0.006	ELANE
pH reduction	1	601.9×	0.006	TCIRG1
establishment of vesicle localization	1	601.9×	0.006	TCIRG1
phagosome acidification	1	601.9×	0.006	TCIRG1
response to yeast	1	526.6×	0.006	ELANE
SRP-dependent cotranslational protein targeting to membrane	1	526.6×	0.006	SRP54
SRP-dependent cotranslational protein targeting to membrane, translocation	1	526.6×	0.006	SRP54
negative regulation of chemokine production	1	526.6×	0.006	ELANE
exocrine pancreas development	1	421.3×	0.007	SRP54
regulation of toll-like receptor signaling pathway	1	383.0×	0.008	GFI1
positive regulation of leukocyte tethering or rolling	1	383.0×	0.008	ELANE
ruffle organization	1	324.1×	0.008	TCIRG1
regulation of osteoblast differentiation	1	324.1×	0.008	TCIRG1
leukocyte migration involved in inflammatory response	1	300.9×	0.008	ELANE

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ELANE	11	4
SRP54	0	0
TCIRG1	0	0
GFI1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE
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): 1.

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

Symbol	Assays	Type breakdown
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
GFI1	6	Binding:6
SRP54	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ELANE	3.4.21.37	leukocyte elastase

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: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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
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)	1	ELANE
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, TCIRG1, GFI1

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	—
TCIRG1	0	—
GFI1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.