Acroosteolysis dominant type

Summary

Acroosteolysis dominant type (MONDO:0007057) is a disease caused by NOTCH2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NOTCH2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,649
• Phenotypes (HPO): 86

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

86 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000704	Periodontitis	Very frequent (80-99%)
HP:0000929	Abnormal skull morphology	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0000939	Osteoporosis	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001831	Short toe	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0004331	Decreased skull ossification	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0011305	Partial absence of toe	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000233	Thin vermilion border	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000269	Prominent occiput	Frequent (30-79%)
HP:0000277	Abnormality of the mandible	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000445	Wide nose	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000470	Short neck	Frequent (30-79%)
HP:0000506	Telecanthus	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Frequent (30-79%)
HP:0002230	Generalized hirsutism	Frequent (30-79%)
HP:0002308	Chiari malformation	Frequent (30-79%)
HP:0002645	Wormian bones	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002688	Absent frontal sinuses	Frequent (30-79%)
HP:0002691	Platybasia	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0004586	Biconcave vertebral bodies	Frequent (30-79%)
HP:0008424	Hypoplastic 5th lumbar vertebrae	Frequent (30-79%)
HP:0010807	Open bite	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acroosteolysis dominant type
Mondo ID	MONDO:0007057
MeSH	C531695, C535663, C537586
OMIM	102500
Orphanet	955
DOID	DOID:2736
NCIT	C84745
SNOMED CT	63122002
UMLS	C0917715
MedGen	182961
GARD	0000508
NORD	1214
Is cancer (heuristic)	no

Also known as: acrodentoosteodysplasia · acroosteolysis with osteoporosis and changes in skull and mandible · Arthrodentoosteodysplasia · Cheney syndrome · Hajdu Cheney Syndrome · Hajdu-Cheney syndrome · Hajdu-Cheney syndrome-NOTCH2 · HJCYS · serpentine fibula polycystic kidney syndrome · serpentine fibula-polycystic kidney syndrome · serpentine fibula-polycystic kidneys syndrome

Data availability: 1,649 ClinVar variants · 5 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 dominant disease › acroosteolysis dominant type

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, 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, autosomal dominant severe congenital neutropenia, 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

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:

292 uncertain significance, 214 likely benign, 32 conflicting classifications of pathogenicity, 25 benign, 19 benign/likely benign, 10 pathogenic, 7 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028812	NM_024408.4(NOTCH2):c.5123_5132delinsAGA (p.Ser1708_Leu1711delinsTer)	NOTCH2	Pathogenic	criteria provided, single submitter
1068831	NM_024408.4(NOTCH2):c.1668C>A (p.Cys556Ter)	NOTCH2	Pathogenic	criteria provided, single submitter
1451302	NM_024408.4(NOTCH2):c.2235_2236del (p.Cys745_Asp746delinsTer)	NOTCH2	Pathogenic	criteria provided, single submitter
1457269	NM_024408.4(NOTCH2):c.3415del (p.Leu1139fs)	NOTCH2	Pathogenic	criteria provided, single submitter
1685986	NM_024408.4(NOTCH2):c.6832dup (p.Thr2278fs)	NOTCH2	Pathogenic	criteria provided, single submitter
1805545	NM_024408.4(NOTCH2):c.6667C>T (p.Gln2223Ter)	NOTCH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1992457	NM_024408.4(NOTCH2):c.7030G>T (p.Glu2344Ter)	NOTCH2	Pathogenic	criteria provided, single submitter
2015161	NM_024408.4(NOTCH2):c.4025_4027delinsTCT (p.Cys1342_Gln1343delinsPheTer)	NOTCH2	Pathogenic	criteria provided, single submitter
2029083	NM_024408.4(NOTCH2):c.901G>T (p.Glu301Ter)	NOTCH2	Pathogenic	criteria provided, single submitter
2127842	NM_024408.4(NOTCH2):c.7099C>T (p.Gln2367Ter)	NOTCH2	Pathogenic	criteria provided, single submitter
223003	NM_024408.4(NOTCH2):c.6909dup (p.Ile2304fs)	NOTCH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1177430	NM_024408.4(NOTCH2):c.3508G>T (p.Gly1170Ter)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1329467	NM_024408.4(NOTCH2):c.6586C>T (p.Gln2196Ter)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1381496	NM_024408.4(NOTCH2):c.6912dup (p.Val2305fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1687415	NM_024408.4(NOTCH2):c.2653dup (p.His885fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1687588	NM_024408.4(NOTCH2):c.6193_6194dup (p.Asn2066fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1690994	NM_024408.4(NOTCH2):c.6450del (p.Val2151fs)	NOTCH2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1993068	NM_024408.4(NOTCH2):c.6274del (p.Leu2092fs)	NOTCH2	Likely pathogenic	criteria provided, single submitter
1017215	NM_024408.4(NOTCH2):c.2785G>A (p.Gly929Arg)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1159787	NM_024408.4(NOTCH2):c.3109G>A (p.Glu1037Lys)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1310937	NM_024408.4(NOTCH2):c.5624G>A (p.Arg1875Gln)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334985	NM_024408.4(NOTCH2):c.5276T>C (p.Val1759Ala)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134965	NM_024408.4(NOTCH2):c.3206G>A (p.Arg1069Gln)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134979	NM_024408.4(NOTCH2):c.5161G>A (p.Ala1721Thr)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134982	NM_024408.4(NOTCH2):c.6979A>G (p.Thr2327Ala)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359168	NM_024408.4(NOTCH2):c.5423C>T (p.Thr1808Ile)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1374353	NM_024408.4(NOTCH2):c.2948A>G (p.His983Arg)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1421156	NM_024408.4(NOTCH2):c.2636C>T (p.Ser879Phe)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1442409	NM_024408.4(NOTCH2):c.1113C>G (p.Leu371=)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1449908	NM_024408.4(NOTCH2):c.2501T>G (p.Leu834Trp)	NOTCH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
NOTCH2	Definitive	Autosomal dominant	acroosteolysis dominant type	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH2	Orphanet:261629	Alagille syndrome due to a NOTCH2 point mutation
NOTCH2	Orphanet:955	Hajdu-Cheney syndrome
HSD3B2	Orphanet:90791	Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase 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
NOTCH2	HGNC:7882	ENSG00000134250	Q04721	Neurogenic locus notch homolog protein 2	gencc,clinvar
ADAM30	HGNC:208	ENSG00000134249	Q9UKF2	Disintegrin and metalloproteinase domain-containing protein 30	clinvar
HSD3B2	HGNC:5218	ENSG00000203859	P26439	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH2	Neurogenic locus notch homolog protein 2	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
ADAM30	Disintegrin and metalloproteinase domain-containing protein 30	Plays a role in lysosomal amyloid precursor protein (APP) processing by cleaving and activating CTSD/cathepsin D which leads to APP degradation.
HSD3B2	3 beta-hydroxysteroid dehydrogenase/Delta 5–>4-isomerase type 2	3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	12.2×	0.230
Scaffold/PPI	1	5.8×	0.230
Enzyme (other)	1	4.0×	0.230

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH2	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
ADAM30	Protease	yes		EGF, Peptidase_M12B, Disintegrin_dom
HSD3B2	Enzyme (other)	yes	1.1.1.145	3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	1
retina	1
skin of hip	1
left testis	1
male germ cell	1
sperm	1
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH2	294	ubiquitous	marker	pigmented layer of retina, retina, skin of hip
ADAM30	15	tissue_specific	yes	sperm, male germ cell, left testis
HSD3B2	157	tissue_specific	yes	right adrenal gland, right adrenal gland cortex, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH2	5,266
HSD3B2	2,968
ADAM30	633

Intra-cohort edges

A	B	Sources
ADAM30	NOTCH2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH2	Q04721	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HSD3B2	P26439	94.30
ADAM30	Q9UKF2	79.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Defective LFNG causes SCDO3	1	761.3×	0.008	NOTCH2
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	634.4×	0.008	NOTCH2
Mineralocorticoid biosynthesis	1	475.8×	0.008	HSD3B2
Androgen biosynthesis	1	346.1×	0.008	HSD3B2
Interaction With Cumulus Cells And The Zona Pellucida	1	346.1×	0.008	ADAM30
Fertilization	1	317.2×	0.008	ADAM30
NOTCH2 intracellular domain regulates transcription	1	317.2×	0.008	NOTCH2
Glucocorticoid biosynthesis	1	292.8×	0.008	HSD3B2
Pre-NOTCH Processing in Golgi	1	211.5×	0.010	NOTCH2
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.010	NOTCH2
Metabolism of steroid hormones	1	173.0×	0.010	HSD3B2
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	146.4×	0.011	NOTCH2
Notch-HLH transcription pathway	1	135.9×	0.011	NOTCH2
Reproduction	1	63.4×	0.021	ADAM30
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.026	NOTCH2
Metabolism of steroids	1	45.9×	0.026	HSD3B2
Pre-NOTCH Transcription and Translation	1	40.9×	0.027	NOTCH2
Metabolism of lipids	1	10.5×	0.097	HSD3B2
Metabolism	1	3.9×	0.237	HSD3B2

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
cholangiocyte proliferation	1	2808.7×	0.006	NOTCH2
regulation of osteoclast development	1	2808.7×	0.006	NOTCH2
intrahepatic bile duct development	1	1872.4×	0.006	NOTCH2
glomerular capillary formation	1	1872.4×	0.006	NOTCH2
ciliary body morphogenesis	1	1404.3×	0.006	NOTCH2
cellular response to tumor cell	1	1404.3×	0.006	NOTCH2
C21-steroid hormone metabolic process	1	1123.5×	0.006	HSD3B2
proximal tubule development	1	1123.5×	0.006	NOTCH2
atrioventricular node development	1	936.2×	0.006	NOTCH2
hepatocyte proliferation	1	702.2×	0.006	NOTCH2
marginal zone B cell differentiation	1	624.1×	0.006	NOTCH2
androgen biosynthetic process	1	624.1×	0.006	HSD3B2
positive regulation of smooth muscle cell differentiation	1	624.1×	0.006	NOTCH2
morphogenesis of an epithelial sheet	1	561.7×	0.007	NOTCH2
podocyte development	1	510.7×	0.007	NOTCH2
placenta blood vessel development	1	468.1×	0.007	NOTCH2
atrial septum morphogenesis	1	432.1×	0.007	NOTCH2
left/right axis specification	1	401.2×	0.007	NOTCH2
positive regulation of keratinocyte proliferation	1	330.4×	0.007	NOTCH2
cell fate determination	1	312.1×	0.007	NOTCH2
inflammatory response to antigenic stimulus	1	312.1×	0.007	NOTCH2
pulmonary valve morphogenesis	1	312.1×	0.007	NOTCH2
myeloid dendritic cell differentiation	1	312.1×	0.007	NOTCH2
bone remodeling	1	312.1×	0.007	NOTCH2
positive regulation of Ras protein signal transduction	1	295.6×	0.007	NOTCH2
steroid biosynthetic process	1	200.6×	0.010	HSD3B2
positive regulation of osteoclast differentiation	1	193.7×	0.010	NOTCH2
positive regulation of BMP signaling pathway	1	151.8×	0.012	NOTCH2
embryonic limb morphogenesis	1	133.8×	0.013	NOTCH2
positive regulation of miRNA transcription	1	96.8×	0.018	NOTCH2

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH2	0	0
ADAM30	0	0
HSD3B2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HSD3B2	3	Binding:3
NOTCH2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HSD3B2	1.1.1.145, 5.3.3.1	3beta-hydroxy-DELTA5-steroid dehydrogenase, steroid DELTA-isomerase

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	2	ADAM30, HSD3B2
E	Difficult family or no structure, no drug	1	NOTCH2

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)
NOTCH2	2	—
ADAM30	0	—
HSD3B2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.