trichorhinophalangeal syndrome type I

Summary

trichorhinophalangeal syndrome type I (MONDO:0008596) is a disease caused by TRPS1 (GenCC Definitive), with 6 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRPS1 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 628
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		250	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000411	Protruding ear	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000653	Sparse eyelashes	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0010049	Short metacarpal	Very frequent (80-99%)
HP:0010579	Cone-shaped epiphysis	Very frequent (80-99%)
HP:0010743	Short metatarsal	Very frequent (80-99%)
HP:0011341	Long upper lip	Very frequent (80-99%)
HP:0011910	Shortening of all phalanges of fingers	Very frequent (80-99%)
HP:0045075	Sparse eyebrow	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001808	Fragile nails	Frequent (30-79%)
HP:0001820	Leukonychia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0005743	Avascular necrosis of the capital femoral epiphysis	Frequent (30-79%)
HP:0011069	Supernumerary tooth	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	trichorhinophalangeal syndrome type I
Mondo ID	MONDO:0008596
MeSH	C536820
OMIM	190350
Orphanet	77258
DOID	DOID:14743
NCIT	C75109
SNOMED CT	254091006
UMLS	C0432233
MedGen	140929
GARD	0007800
NORD	1787
Is cancer (heuristic)	no

Also known as: Giedion syndrome · Sugio-Kajii syndrome · trichorhinophalangeal dysplasia (syndrome) types 1/3 · trichorhinophalangeal dysplasia type I · trichorhinophalangeal dysplasia types 1/3 · trichorhinophalangeal syndrome type 1 · trichorhinophalangeal syndrome type I · trichorhinophalangeal syndrome, type 1 · trichorhinophalangeal syndrome, type I · TRPS 1 · TRPS1 · type III trichorhinophalangeal syndrome

Data availability: 628 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

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 › trichorhinophalangeal syndrome type I

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, 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:

198 uncertain significance, 170 likely benign, 113 pathogenic, 34 benign, 30 conflicting classifications of pathogenicity, 23 likely pathogenic, 17 not provided, 10 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3245509	NC_000008.10:g.(?116426251)(120844804_?)del	AARD	Pathogenic	criteria provided, single submitter
1703572	GRCh37/hg19 8q23.3-24.11(chr8:115662767-117718250)	EIF3H	Pathogenic	no assertion criteria provided
438454	NG_012383.3:g.(70130_86397)_(87002_255549)dup	LOC110120802	Pathogenic	no assertion criteria provided
438455	NG_012383.3:g.(70130_86397)_(87002_255549)del	LOC110120802	Pathogenic	no assertion criteria provided
438459	NG_012383.3:g.(87002_255549)(259980?)del	LOC110120802	Pathogenic	no assertion criteria provided
599306	Single allele	MYC	Pathogenic	criteria provided, single submitter
1069269	NM_014112.5(TRPS1):c.2657C>A (p.Ser886Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1069769	NM_014112.5(TRPS1):c.913C>T (p.Gln305Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1069963	NM_014112.5(TRPS1):c.612_615dup (p.Gly206fs)	TRPS1	Pathogenic	criteria provided, single submitter
1070473	NM_014112.5(TRPS1):c.1911del (p.Asp638fs)	TRPS1	Pathogenic	criteria provided, single submitter
1074212	NM_014112.5(TRPS1):c.2757_2758del (p.Trp920fs)	TRPS1	Pathogenic	criteria provided, single submitter
1075041	NM_014112.5(TRPS1):c.2453C>A (p.Ser818Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1076208	NM_014112.5(TRPS1):c.2300_2301del (p.Asp766_Ser767insTer)	TRPS1	Pathogenic	criteria provided, single submitter
1187428	NM_014112.5(TRPS1):c.2194C>T (p.Gln732Ter)	TRPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1224423	NM_014112.5(TRPS1):c.2374A>T (p.Lys792Ter)	TRPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299557	NM_014112.5(TRPS1):c.2090dup (p.His697fs)	TRPS1	Pathogenic	criteria provided, single submitter
1345055	NM_014112.5(TRPS1):c.2786T>G (p.Val929Gly)	TRPS1	Pathogenic	criteria provided, single submitter
1362155	NM_014112.5(TRPS1):c.1777G>T (p.Glu593Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1364143	NM_014112.5(TRPS1):c.1402del (p.Tyr468fs)	TRPS1	Pathogenic	criteria provided, single submitter
1366100	NM_014112.5(TRPS1):c.1690C>T (p.Gln564Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1381794	NM_014112.5(TRPS1):c.3248del (p.Lys1083fs)	TRPS1	Pathogenic	criteria provided, single submitter
1396687	NM_014112.5(TRPS1):c.2829del (p.Arg944fs)	TRPS1	Pathogenic	criteria provided, single submitter
1427092	NM_014112.5(TRPS1):c.964C>T (p.Gln322Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1451506	NM_014112.5(TRPS1):c.2188C>T (p.Gln730Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1451536	NM_014112.5(TRPS1):c.1646_1649dup (p.Pro551fs)	TRPS1	Pathogenic	criteria provided, single submitter
1452663	NM_014112.5(TRPS1):c.3268_3275del (p.His1090fs)	TRPS1	Pathogenic	criteria provided, single submitter
1456376	NC_000008.10:g.(?116599208)(116635864_?)dup	TRPS1	Pathogenic	criteria provided, single submitter
1456401	NM_014112.5(TRPS1):c.2152C>T (p.Gln718Ter)	TRPS1	Pathogenic	criteria provided, single submitter
1457916	NM_014112.5(TRPS1):c.596del (p.Asn199fs)	TRPS1	Pathogenic	criteria provided, single submitter
1458518	NM_014112.5(TRPS1):c.1387A>T (p.Lys463Ter)	TRPS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
TRPS1	Definitive	Autosomal dominant	trichorhinophalangeal syndrome type I	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
MYC	Orphanet:480541	High grade B-cell lymphoma with MYC and/ or BCL2 and/or BCL6 rearrangement
MYC	Orphanet:543	Burkitt lymphoma
MYC	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	gencc,clinvar
EIF3H	HGNC:3273	ENSG00000147677	O15372	Eukaryotic translation initiation factor 3 subunit H	clinvar
AARD	HGNC:33842	ENSG00000205002	Q4LEZ3	Alanine- and arginine-rich domain-containing protein	clinvar
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	clinvar
MYC	HGNC:7553	ENSG00000136997	P01106	Myc proto-oncogene protein	clinvar
ACADL	HGNC:88	ENSG00000115361	P28330	Long-chain specific acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
EIF3H	Eukaryotic translation initiation factor 3 subunit H	Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
MYC	Myc proto-oncogene protein	Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5’-CAC[GA]TG-3'.
ACADL	Long-chain specific acyl-CoA dehydrogenase, mitochondrial	Long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of energy…

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.33

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	6.1×	0.264
Kinase	1	4.6×	0.264
Transcription factor	2	2.8×	0.264
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
EIF3H	Protease	yes		JAMM/MPN+_dom, eIF3h, MPN
AARD	Other/Unknown	no		FAM167_domain
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
MYC	Transcription factor	no		Tscrpt_reg_Myc, Myc-LZ, bHLH_dom
ACADL	Other/Unknown	no		Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
epithelium of mammary gland	1
mammary duct	1
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1
left testis	1
right testis	1
testis	1
cranial nerve II	1
endothelial cell	1
secondary oocyte	1
left uterine tube	1
upper leg skin	1
vena cava	1
body of pancreas	1
popliteal artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
EIF3H	299	ubiquitous	marker	cortical plate, ganglionic eminence, primordial germ cell in gonad
AARD	116	broad	marker	left testis, testis, right testis
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II
MYC	256	ubiquitous	marker	upper leg skin, vena cava, left uterine tube
ACADL	208	broad	marker	body of pancreas, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYC	20,608
ERBB4	4,325
EIF3H	3,091
TRPS1	2,588
ACADL	2,251
AARD	279

Intra-cohort edges

A	B	Sources
EIF3H	TRPS1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF3H	O15372	27
MYC	P01106	25
ERBB4	Q15303	14
ACADL	P28330	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AARD	Q4LEZ3	78.24
TRPS1	Q9UHF7	49.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 95. Enrichment computed across 6 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
Beta oxidation of myristoyl-CoA to lauroyl-CoA	1	951.7×	0.030	ACADL
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	571.0×	0.030	ACADL
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	571.0×	0.030	MYC
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	475.8×	0.030	ACADL
mitochondrial fatty acid beta-oxidation of saturated fatty acids	1	407.9×	0.030	ACADL
Regulation of NFE2L2 gene expression	1	356.9×	0.030	MYC
Downregulation of ERBB4 signaling	1	285.5×	0.030	ERBB4
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	285.5×	0.030	MYC
RUNX3 regulates WNT signaling	1	285.5×	0.030	MYC
PI3K events in ERBB4 signaling	1	259.6×	0.030	ERBB4
Regulation of CDH1 mRNA translation by microRNAs	1	259.6×	0.030	MYC
Estrogen-dependent gene expression	2	37.8×	0.030	ERBB4, MYC
ERBB2 Activates PTK6 Signaling	1	203.9×	0.031	ERBB4
SHC1 events in ERBB4 signaling	1	178.4×	0.031	ERBB4
Repression of WNT target genes	1	178.4×	0.031	MYC
ERBB2 Regulates Cell Motility	1	178.4×	0.031	ERBB4
PI3K events in ERBB2 signaling	1	167.9×	0.031	ERBB4
GRB2 events in ERBB2 signaling	1	158.6×	0.031	ERBB4
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	158.6×	0.031	MYC
Signaling by ALK	1	142.8×	0.031	MYC
Transcription of E2F targets under negative control by DREAM complex	1	135.9×	0.031	MYC
SHC1 events in ERBB2 signaling	1	119.0×	0.031	ERBB4
Long-term potentiation	1	119.0×	0.031	ERBB4
Signaling by ERBB2 TMD/JMD mutants	1	119.0×	0.031	ERBB4
G0 and Early G1	1	109.8×	0.031	MYC
Signaling by ERBB2 KD Mutants	1	105.7×	0.031	ERBB4
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	102.0×	0.031	MYC
Signaling by NOTCH1 in Cancer	1	102.0×	0.031	MYC
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	102.0×	0.031	MYC
Mitochondrial Fatty Acid Beta-Oxidation	1	95.2×	0.031	ACADL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
carnitine catabolic process	1	2808.7×	0.008	ACADL
positive regulation of metanephric cap mesenchymal cell proliferation	1	2808.7×	0.008	MYC
positive regulation of acinar cell proliferation	1	2808.7×	0.008	MYC
acinar cell proliferation	1	2808.7×	0.008	MYC
positive regulation of epithelial cell proliferation	2	81.4×	0.008	ERBB4, MYC
central nervous system morphogenesis	1	1404.3×	0.011	ERBB4
establishment of planar polarity involved in nephron morphogenesis	1	1404.3×	0.011	ERBB4
NK T cell proliferation	1	936.2×	0.012	MYC
carnitine metabolic process, CoA-linked	1	936.2×	0.012	ACADL
protein-DNA complex disassembly	1	936.2×	0.012	MYC
positive regulation of B cell apoptotic process	1	702.2×	0.012	MYC
rRNA metabolic process	1	702.2×	0.012	MYC
cardiac muscle tissue regeneration	1	702.2×	0.012	ERBB4
olfactory bulb interneuron differentiation	1	561.7×	0.012	ERBB4
negative regulation of transcription initiation by RNA polymerase II	1	561.7×	0.012	MYC
regulation of somatic stem cell population maintenance	1	561.7×	0.012	MYC
ERBB4 signaling pathway	1	468.1×	0.012	ERBB4
ERBB2-ERBB4 signaling pathway	1	468.1×	0.012	ERBB4
long-chain fatty acid catabolic process	1	468.1×	0.012	ACADL
positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	468.1×	0.012	MYC
ERBB4-ERBB4 signaling pathway	1	401.2×	0.012	ERBB4
negative regulation of monocyte differentiation	1	401.2×	0.012	MYC
negative regulation of cell division	1	401.2×	0.012	MYC
myotube differentiation	1	351.1×	0.013	MYC
negative regulation of stress-activated MAPK cascade	1	280.9×	0.014	MYC
negative regulation of fatty acid oxidation	1	280.9×	0.014	ACADL
cellular response to interferon-alpha	1	255.3×	0.014	MYC
response to alkaloid	1	255.3×	0.014	MYC
fibroblast apoptotic process	1	255.3×	0.014	MYC
B cell apoptotic process	1	234.1×	0.014	MYC

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 4

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
ERBB4	MOBOCERTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERBB4	47	4
MYC	3	3
TRPS1	0	0
EIF3H	0	0
AARD	0	0
ACADL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
FEDRATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4
BOSUTINIB	4	ERBB4
BRIGATINIB	4	ERBB4
ACALABRUTINIB	4	ERBB4
ZANUBRUTINIB	4	ERBB4
TIRABRUTINIB	4	ERBB4
RITLECITINIB	4	ERBB4
DASATINIB	4	ERBB4
ERLOTINIB	4	ERBB4
LAPATINIB	4	ERBB4
MIDOSTAURIN	4	ERBB4
GEFITINIB	4	ERBB4
CANERTINIB	3	ERBB4
EVOBRUTINIB	3	ERBB4
ALVOCIDIB	3	ERBB4
REMIBRUTINIB	3	ERBB4
ALISERTIB	3	ERBB4
CEDIRANIB	3	ERBB4
CANERTINIB DIHYDROCHLORIDE	3	ERBB4
LESTAURTINIB	3	ERBB4
RESVERATROL	3	MYC
AEE-788	2	ERBB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ERBB4	591	Binding:579, ADMET:8, Functional:4
MYC	202	Binding:202
EIF3H	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERBB4	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ERBB4	591
MYC	202

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
FEDRATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4
BOSUTINIB	4	ERBB4
BRIGATINIB	4	ERBB4
ACALABRUTINIB	4	ERBB4
ZANUBRUTINIB	4	ERBB4
TIRABRUTINIB	4	ERBB4
RITLECITINIB	4	ERBB4
DASATINIB	4	ERBB4
ERLOTINIB	4	ERBB4
LAPATINIB	4	ERBB4
MIDOSTAURIN	4	ERBB4
GEFITINIB	4	ERBB4
CANERTINIB	3	ERBB4
EVOBRUTINIB	3	ERBB4
ALVOCIDIB	3	ERBB4
REMIBRUTINIB	3	ERBB4
ALISERTIB	3	ERBB4
CEDIRANIB	3	ERBB4
CANERTINIB DIHYDROCHLORIDE	3	ERBB4
LESTAURTINIB	3	ERBB4
RESVERATROL	3	MYC
AEE-788	2	ERBB4

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERBB4
B	Phased (≥1) drug, not yet approved	1	MYC
C	Druggable family + PDB, no drug	1	EIF3H
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TRPS1, AARD, ACADL

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)
TRPS1	0	—
EIF3H	1	—
AARD	0	—
ACADL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.