Beckwith-Wiedemann syndrome

disease

On this page

Also known as BWSexomphalos macroglossia gigantism syndromeexomphalos-macroglossia-gigantism syndromeWiedemann-Beckwith syndromeWiedemann-Beckwith syndrome (WBS)

Summary

Beckwith-Wiedemann syndrome (MONDO:0007534) is a disease (an umbrella term covering 8 Mondo subtypes) caused by variants in CDKN1C, H19, and NLRP5, with 14 cohort genes and 6 clinical trials. Top therapeutic interventions include dactinomycin, doxorubicin hydrochloride, and fluorodopa f 18.

At a glance

Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
Causal genes: CDKN1C (GenCC Definitive), H19 (GenCC Strong), NLRP5 (GenCC Strong)
Umbrella term: 8 Mondo subtypes
Cohort genes: 14
ClinVar variants: 1,358
Phenotypes (HPO): 85
Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3.5	Europe	Validated
Prevalence at birth	1-9 / 100 000	1.3	Spain	Validated
Prevalence at birth	1-9 / 100 000	5.25	Japan	Validated
Prevalence at birth	1-9 / 100 000	7.4	Jamaica	Validated
Prevalence at birth	1-5 / 10 000	10	Italy	Validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000098	Tall stature	Very frequent (80-99%)
HP:0001520	Large for gestational age	Very frequent (80-99%)
HP:0002664	Neoplasm	Very frequent (80-99%)
HP:0000105	Enlarged kidney	Frequent (30-79%)
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0000269	Prominent occiput	Frequent (30-79%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000363	Abnormality of earlobe	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000776	Congenital diaphragmatic hernia	Frequent (30-79%)
HP:0000842	Hyperinsulinemia	Frequent (30-79%)
HP:0000995	Melanocytic nevus	Frequent (30-79%)
HP:0001052	Nevus flammeus	Frequent (30-79%)
HP:0001139	Choroideremia	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001528	Hemihypertrophy	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001539	Omphalocele	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001582	Redundant skin	Frequent (30-79%)
HP:0001622	Premature birth	Frequent (30-79%)
HP:0001738	Exocrine pancreatic insufficiency	Frequent (30-79%)
HP:0001943	Hypoglycemia	Frequent (30-79%)
HP:0001998	Neonatal hypoglycemia	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0003271	Visceromegaly	Frequent (30-79%)
HP:0004464	Postauricular pit	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0006267	Large placenta	Frequent (30-79%)
HP:0008523	Posterior helix pit	Frequent (30-79%)
HP:0008659	Multiple small medullary renal cysts	Frequent (30-79%)
HP:0009908	Anterior creases of earlobe	Frequent (30-79%)
HP:0011417	Long umbilical cord	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0030720	Subchorionic septal cyst	Frequent (30-79%)
HP:0031510	Linear earlobe crease	Frequent (30-79%)
HP:0100555	Asymmetric growth	Frequent (30-79%)
HP:0100876	Infra-orbital crease	Frequent (30-79%)
HP:0000309	Abnormal midface morphology	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000073	Ureteral duplication	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000150	Gonadoblastoma	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Beckwith-Wiedemann syndrome
Mondo ID	MONDO:0007534
MeSH	D001506
OMIM	130650
Orphanet	116
DOID	DOID:5572
ICD-11	803086260
NCIT	C34415
SNOMED CT	81780002
UMLS	C0004903
MedGen	2562
GARD	0003343
MedDRA	10050344
NORD	845
Is cancer (heuristic)	no

Also known as: Beckwith-Wiedemann syndrome · BWS · exomphalos macroglossia gigantism syndrome · exomphalos-macroglossia-gigantism syndrome · Wiedemann-Beckwith syndrome · Wiedemann-Beckwith syndrome (WBS)

Data availability: 1,358 ClinVar variants · 9 GenCC gene-disease records · 9 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Subtypes (8): Beckwith-Wiedemann syndrome due to imprinting defect of 11p15, Beckwith-Wiedemann syndrome due to CDKN1C mutation, Beckwith-Wiedemann syndrome due to 11p15 microdeletion, Beckwith-Wiedemann syndrome due to 11p15 translocation/inversion, Beckwith-Wiedemann syndrome due to NSD1 mutation, Beckwith-Wiedemann syndrome due to 11p15 microduplication, Beckwith-Wiedemann syndrome due to paternal uniparental disomy of chromosome 11, Franceschini Vardeu Guala 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:

264 likely benign, 251 uncertain significance, 55 pathogenic, 14 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 pathogenic/likely pathogenic, 3 likely pathogenic, 1 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070416	NM_001122630.2(CDKN1C):c.199C>T (p.Gln67Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1071226	NM_001122630.2(CDKN1C):c.399_415del (p.Ala134fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1071455	NM_001122630.2(CDKN1C):c.325G>T (p.Glu109Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1072486	NM_001122630.2(CDKN1C):c.203G>A (p.Trp68Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1074899	NM_001122630.2(CDKN1C):c.95_96insA (p.Ser32fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1076545	NM_001122630.2(CDKN1C):c.748_749del (p.Gly250fs)	CDKN1C	Pathogenic	criteria provided, single submitter
132842	NM_001122630.2(CDKN1C):c.176C>T (p.Pro59Leu)	CDKN1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132848	NM_001122630.2(CDKN1C):c.300dup (p.Ala101fs)	CDKN1C	Pathogenic	no assertion criteria provided
132850	NM_001122630.2(CDKN1C):c.367dup (p.Glu123fs)	CDKN1C	Pathogenic	no assertion criteria provided
132861	NM_001122630.2(CDKN1C):c.655C>T (p.Gln219Ter)	CDKN1C	Pathogenic	criteria provided, multiple submitters, no conflicts
132864	NM_001122630.2(CDKN1C):c.688C>T (p.Gln230Ter)	CDKN1C	Pathogenic	criteria provided, multiple submitters, no conflicts
132866	NM_001122630.2(CDKN1C):c.698C>A (p.Ser233Ter)	CDKN1C	Pathogenic	criteria provided, multiple submitters, no conflicts
1372013	NM_001122630.2(CDKN1C):c.193_200dup (p.Gln67fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1372071	NM_001122630.2(CDKN1C):c.205del (p.Thr69fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1374542	NM_001122630.2(CDKN1C):c.745_757del (p.Asn249fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1379126	NM_001122630.2(CDKN1C):c.60_61del (p.Ser21fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1391208	NM_001122630.2(CDKN1C):c.809_810del (p.Arg270fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1396638	NM_001122630.2(CDKN1C):c.204G>A (p.Trp68Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1401271	NM_001122630.2(CDKN1C):c.244G>T (p.Glu82Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1402309	NM_001122630.2(CDKN1C):c.578del (p.Pro193fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1411126	NM_001122630.2(CDKN1C):c.57C>A (p.Cys19Ter)	CDKN1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417762	NM_001122630.2(CDKN1C):c.410del (p.Pro137fs)	CDKN1C	Pathogenic	criteria provided, multiple submitters, no conflicts
143246	NM_001122630.2(CDKN1C):c.*5+2T>C	CDKN1C	Pathogenic	no assertion criteria provided
1454485	NC_000011.9:g.(?2905228)(2906725_?)del	CDKN1C	Pathogenic	criteria provided, single submitter
1454500	NM_001122630.2(CDKN1C):c.132del (p.Glu45fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1455010	NM_001122630.2(CDKN1C):c.133G>T (p.Glu45Ter)	CDKN1C	Pathogenic	criteria provided, single submitter
1455648	NM_001122630.2(CDKN1C):c.174dup (p.Pro59fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1455977	NM_001122630.2(CDKN1C):c.421_422insA (p.Pro141fs)	CDKN1C	Pathogenic	criteria provided, single submitter
1708131	NM_001122630.2(CDKN1C):c.832_835delinsCTGCGCCTGA (p.Gly278_Asp279delinsLeuArgLeuAsn)	CDKN1C	Pathogenic	criteria provided, single submitter
18445	NM_001122630.2(CDKN1C):c.812C>G (p.Ser271Ter)	CDKN1C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 37 · 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
CDKN1C	Definitive	Autosomal dominant	Beckwith-Wiedemann syndrome	12
H19	Strong	Autosomal dominant	Beckwith-Wiedemann syndrome	2
NLRP5	Strong	Autosomal recessive	Beckwith-Wiedemann syndrome	3
KCNQ1OT1	Limited	Unknown	Beckwith-Wiedemann syndrome	2
ZNF215	No Known Disease Relationship	Unknown	Beckwith-Wiedemann syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDKN1C	Orphanet:231120	Beckwith-Wiedemann syndrome due to CDKN1C mutation
CDKN1C	Orphanet:397590	Silver-Russell syndrome due to a point mutation
CDKN1C	Orphanet:436144	Intrauterine growth restriction-short stature-early adult-onset diabetes syndrome
CDKN1C	Orphanet:85173	IMAGe syndrome
H19	Orphanet:2128	Isolated hemihyperplasia
H19	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
H19	Orphanet:231127	Beckwith-Wiedemann syndrome due to 11p15 microdeletion
H19	Orphanet:231140	Silver-Russell syndrome due to an imprinting defect of 11p15
H19	Orphanet:231144	Silver-Russell syndrome due to 11p15 microduplication
H19	Orphanet:654	Nephroblastoma
KCNQ1OT1	Orphanet:2128	Isolated hemihyperplasia
KCNQ1OT1	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
NSD1	Orphanet:1627	Deletion 5q35 syndrome
NSD1	Orphanet:228415	5q35 microduplication syndrome
NSD1	Orphanet:3447	Weaver syndrome
NSD1	Orphanet:821	Sotos syndrome
CTSD	Orphanet:700487	Congenital CLN10 disease
CTSD	Orphanet:700492	Late infantile CLN10 disease
CTSD	Orphanet:700497	Juvenile CLN10 disease
DNMT1	Orphanet:314404	Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome
DNMT1	Orphanet:456318	Hereditary sensory neuropathy-deafness-dementia syndrome
IGF2	Orphanet:2128	Isolated hemihyperplasia
IGF2	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15
IGF2	Orphanet:231140	Silver-Russell syndrome due to an imprinting defect of 11p15
IGF2	Orphanet:231144	Silver-Russell syndrome due to 11p15 microduplication
IGF2	Orphanet:397590	Silver-Russell syndrome due to a point mutation
KCNQ1	Orphanet:101016	Romano-Ward syndrome
KCNQ1	Orphanet:334	Hereditary atrial fibrillation
KCNQ1	Orphanet:51083	Congenital short QT syndrome
KCNQ1	Orphanet:90647	Jervell and Lange-Nielsen syndrome

Cohort genes → proteins

14 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDKN1C	HGNC:1786	ENSG00000129757	P49918	Cyclin-dependent kinase inhibitor 1C	gencc,clinvar
H19	HGNC:4713	ENSG00000130600		H19 imprinted maternally expressed transcript	gencc,clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 1	gencc,clinvar
ZNF215	HGNC:13007	ENSG00000149054	Q9UL58	Zinc finger protein 215	gencc
NLRP5	HGNC:21269	ENSG00000171487	P59047	NACHT, LRR and PYD domains-containing protein 5	gencc
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
NSD1	HGNC:14234	ENSG00000165671	Q96L73	Histone-lysine N-methyltransferase, H3 lysine-36 specific	clinvar
ANO9	HGNC:20679	ENSG00000185101	A1A5B4	Anoctamin-9	clinvar
CTSD	HGNC:2529	ENSG00000117984	P07339	Cathepsin D	clinvar
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	clinvar
IGF2	HGNC:5466	ENSG00000167244	P01344	Insulin-like growth factor 2	clinvar
IGF2R	HGNC:5467	ENSG00000197081	P11717	Cation-independent mannose-6-phosphate receptor	clinvar
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	clinvar
POLR2F	HGNC:9193	ENSG00000100142	P61218	DNA-directed RNA polymerases I, II, and III subunit RPABC2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDKN1C	Cyclin-dependent kinase inhibitor 1C	Potent tight-binding inhibitor of several G1 cyclin/CDK complexes (cyclin E-CDK2, cyclin D2-CDK4, and cyclin A-CDK2) and, to lesser extent, of the mitotic cyclin B-CDC2.
ZNF215	Zinc finger protein 215	May be involved in transcriptional regulation.
NLRP5	NACHT, LRR and PYD domains-containing protein 5	Component of the subcortical maternal complex (SCMC), a multiprotein complex that plays a key role in early embryonic development.
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
NSD1	Histone-lysine N-methyltransferase, H3 lysine-36 specific	Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2).
ANO9	Anoctamin-9	PKA-activated nonselective cation channel.
CTSD	Cathepsin D	Acid protease active in intracellular protein breakdown.
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.
IGF2	Insulin-like growth factor 2	The insulin-like growth factors possess growth-promoting activity.
IGF2R	Cation-independent mannose-6-phosphate receptor	Mediates the transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes.
KCNQ1	Potassium voltage-gated channel subfamily KQT member 1	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon.
POLR2F	DNA-directed RNA polymerases I, II, and III subunit RPABC2	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 8 · Druggable fraction: 0.21

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
Ion channel	1	8.0×	0.393
Transporter	1	5.6×	0.393
Transcription factor	3	1.8×	0.393
Protease	1	2.6×	0.402
Other/Unknown	8	1.0×	0.571

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDKN1C	Other/Unknown	no		CDI_dom, CDI_dom_sf
H19	Other/Unknown	no
KCNQ1OT1	Other/Unknown	no
ZNF215	Transcription factor	no		KRAB, SCAN_dom, Znf_C2H2_type
NLRP5	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
NSD1	Transcription factor	no	2.1.1.357	PWWP_dom, SET_dom, Znf_PHD
ANO9	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
CTSD	Protease	yes	3.4.23.5	Aspartic_peptidase_A1, Aspartic_peptidase_AS, Aspartic_peptidase_N
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
IGF2	Other/Unknown	no		IGF2_C, Insulin-like, IGF2
IGF2R	Other/Unknown	no		CIMR_rpt, FN_type2_dom, Man6P_isomerase_rcpt-bd_dom_sf
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
POLR2F	Other/Unknown	no		Pol_omega/Rpo6/RPB6, Rpo6/Rpb6, DNA-dir_RNA_polK_14-18kDa_CS

Expression context

Cohort genes with no expression data: 0.

14 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	4
adrenal tissue	3
placenta	3
oocyte	3
secondary oocyte	3
C1 segment of cervical spinal cord	2
skin of abdomen	2
tibial nerve	2
left adrenal gland	2
right adrenal gland cortex	2
hindlimb stylopod muscle	1
cardiac muscle of right atrium	1
kidney epithelium	1
tibia	1
primordial germ cell in gonad	1
male germ line stem cell (sensu Vertebrata) in testis	1
calcaneal tendon	1
colonic epithelium	1
mucosa of transverse colon	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDKN1C	134	ubiquitous	marker	placenta, adrenal tissue, C1 segment of cervical spinal cord
H19	134	broad	marker	placenta, adrenal tissue, hindlimb stylopod muscle
KCNQ1OT1	194	ubiquitous	marker	tibia, cardiac muscle of right atrium, kidney epithelium
ZNF215	171	broad	marker	secondary oocyte, oocyte, primordial germ cell in gonad
NLRP5	22		marker	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
NSD1	235	ubiquitous	marker	sural nerve, colonic epithelium, calcaneal tendon
ANO9	184	broad	marker	mucosa of transverse colon, upper arm skin, skin of abdomen
CTSD	290	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
DNMT1	266	ubiquitous	marker	oocyte, secondary oocyte, sural nerve
IGF2	135	ubiquitous	marker	adrenal tissue, placenta, sural nerve
IGF2R	285	ubiquitous	marker	stromal cell of endometrium, gastrocnemius, granulocyte
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
POLR2F	293	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
SLC2A1	5,711
IGF2	4,294
CTSD	4,280
IGF2R	3,464
KCNQ1	3,235
NSD1	2,979
CDKN1C	2,275
NLRP5	1,057
ZNF215	638

Intra-cohort edges

A	B	Sources
CDKN1C	IGF2	string_interaction
CDKN1C	KCNQ1	string_interaction
CTSD	IGF2R	string_interaction
IGF2	IGF2R	intact, string_interaction
IGF2	ZNF215	string_interaction
NSD1	ZNF215	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60
KCNQ1	P51787	28
DNMT1	P26358	27
IGF2R	P11717	24
IGF2	P01344	16
CTSD	P07339	9
SLC2A1	P11166	5
NSD1	Q96L73	4
NLRP5	P59047	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO9	A1A5B4	80.99
CDKN1C	P49918	63.93
ZNF215	Q9UL58	49.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 156. Enrichment computed across 14 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	1038.2×	0.086	SLC2A1
Lactose synthesis	1	346.1×	0.086	SLC2A1
Vitamin C (ascorbate) metabolism	1	129.8×	0.086	SLC2A1
SHC-related events triggered by IGF1R	1	103.8×	0.086	IGF2
Phase 3 - rapid repolarisation	1	103.8×	0.086	KCNQ1
IRS-related events triggered by IGF1R	1	94.4×	0.086	IGF2
STAT3 nuclear events downstream of ALK signaling	1	94.4×	0.086	DNMT1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	86.5×	0.086	IGF2
Signaling by Insulin receptor	1	79.9×	0.086	CTSD
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	1	79.9×	0.086	CDKN1C
Induction of Cell-Cell Fusion	1	79.9×	0.086	ANO9
FGFR2 mutant receptor activation	1	69.2×	0.086	POLR2F
Phase 2 - plateau phase	1	69.2×	0.086	KCNQ1
SUMOylation of DNA methylation proteins	1	61.1×	0.086	DNMT1
Metabolism of Angiotensinogen to Angiotensins	1	57.7×	0.086	CTSD
RNA Polymerase III Chain Elongation	1	57.7×	0.086	POLR2F
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	1	57.7×	0.086	CDKN1C
Signaling by FGFR2 IIIa TM	1	54.6×	0.086	POLR2F
Cellular hexose transport	1	49.4×	0.086	SLC2A1
Abortive elongation of HIV-1 transcript in the absence of Tat	1	45.1×	0.086	POLR2F
RNA Polymerase III Transcription Termination	1	45.1×	0.086	POLR2F
MicroRNA (miRNA) biogenesis	1	41.5×	0.086	POLR2F
Activation of HOX genes during differentiation	1	39.9×	0.086	POLR2F
Signaling by FGFR in disease	1	38.5×	0.086	POLR2F
FGFR2 alternative splicing	1	38.5×	0.086	POLR2F
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	38.5×	0.086	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	37.1×	0.086	POLR2F
Signaling by FGFR2	1	37.1×	0.086	POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	37.1×	0.086	POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	37.1×	0.086	POLR2F

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic placenta morphogenesis	2	561.7×	8e-04	CDKN1C, IGF2
genomic imprinting	2	165.2×	0.005	CDKN1C, IGF2
gastrin-induced gastric acid secretion	1	1404.3×	0.016	KCNQ1
regulation of peptidyl-serine phosphorylation	1	1404.3×	0.016	NSD1
epigenetic programming of gene expression	1	1404.3×	0.016	DNMT1
regulation of RNA polymerase II regulatory region sequence-specific DNA binding	1	1404.3×	0.016	NSD1
negative regulation of voltage-gated potassium channel activity	1	1404.3×	0.016	KCNQ1
rhythmic behavior	1	702.2×	0.016	KCNQ1
corticosterone secretion	1	702.2×	0.016	KCNQ1
cortical granule exocytosis	1	702.2×	0.016	NLRP5
stomach development	1	702.2×	0.016	KCNQ1
regulation of lens fiber cell differentiation	1	702.2×	0.016	CDKN1C
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	702.2×	0.016	DNMT1
glucose metabolic process	2	42.6×	0.016	IGF2, KCNQ1
response to insulin	2	38.5×	0.016	SLC2A1, KCNQ1
establishment of organelle localization	1	468.1×	0.017	NLRP5
regulation of gastric acid secretion	1	468.1×	0.017	KCNQ1
calcium activated galactosylceramide scrambling	1	468.1×	0.017	ANO9
response to Thyroglobulin triiodothyronine	1	468.1×	0.017	SLC2A1
negative regulation of vascular associated smooth muscle cell apoptotic process	1	468.1×	0.017	DNMT1
long-chain fatty acid import across plasma membrane	1	351.1×	0.017	SLC2A1
insulin receptor recycling	1	351.1×	0.017	CTSD
GDP-L-fucose salvage	1	351.1×	0.017	SLC2A1
calcium activated phosphatidylserine scrambling	1	351.1×	0.017	ANO9
chromosomal DNA methylation maintenance following DNA replication	1	351.1×	0.017	DNMT1
insulin catabolic process	1	351.1×	0.017	CTSD
response to tetrachloromethane	1	351.1×	0.017	IGF2R
methylation	2	28.4×	0.017	NSD1, DNMT1
positive regulation of skeletal muscle tissue growth	1	280.9×	0.018	IGF2
digestive system development	1	280.9×	0.018	CDKN1C

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 9

Druggability breadth: 7 of 14 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
SLC2A1	EMETINE
NSD1	VENETOCLAX
CTSD	AMPRENAVIR
DNMT1	DECITABINE
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ1	15	4
CTSD	8	4
SLC2A1	7	4
NSD1	7	4
DNMT1	6	4
CDKN1C	0	0
H19	0	0
KCNQ1OT1	0	0
ZNF215	0	0
NLRP5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EMETINE	4	SLC2A1
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
GOSSYPOL	3	SLC2A1
SURAMIN	3	NSD1
EPIGALOCATECHIN GALLATE	3	DNMT1
VOLINANSERIN	3	KCNQ1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	DNMT1, SLC2A1
COLFORSIN	2	SLC2A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
CTSD	352	Binding:331, ADMET:15, Toxicity:3, Functional:3
DNMT1	233	Binding:229, Functional:3, ADMET:1
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
SLC2A1	158	Binding:130, ADMET:24, Functional:4
NSD1	90	Binding:90
IGF2R	5	Binding:4, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD1	2.1.1.357, 2.1.1.362	[histone H3]-lysine36 N-dimethyltransferase, [histone H4]-N-methyl-L-lysine20 N-methyltransferase
CTSD	3.4.23.5	cathepsin D
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC2A1	158
CTSD	352
DNMT1	233
KCNQ1	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
EMETINE	4	SLC2A1
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
AMPRENAVIR	4	CTSD
TIPRANAVIR	4	CTSD
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
GOSSYPOL	3	SLC2A1
SURAMIN	3	NSD1
EPIGALOCATECHIN GALLATE	3	DNMT1
VOLINANSERIN	3	KCNQ1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	DNMT1, SLC2A1
COLFORSIN	2	SLC2A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	SLC2A1, NSD1, CTSD, DNMT1, KCNQ1
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	9	CDKN1C, H19, KCNQ1OT1, ZNF215, NLRP5, ANO9, IGF2, IGF2R, POLR2F

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN1C	0	KCNQ1
H19	0	—
KCNQ1OT1	0	—
ZNF215	0	—
NLRP5	0	—
ANO9	0	—
IGF2	0	—
IGF2R	5	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01916148	Not specified	AVAILABLE	18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT06346418	Not specified	RECRUITING	Maternal Genes and Epimutations: Beckwith-Wiedemann Syndrome & Reproductive Risks
NCT04993235	Not specified	UNKNOWN	Body Perception and Representation in Overgrowth Syndromes, Behavioral Assessment and Neuropsychological Development

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DACTINOMYCIN	4	1
DOXORUBICIN HYDROCHLORIDE	4	1
FLUORODOPA F 18	4	1
CHEMBL4748391	0	1

Cohort genes: CDKN1C, H19, KCNQ1OT1, ZNF215, NLRP5, SLC2A1, NSD1, ANO9, CTSD, DNMT1, IGF2, IGF2R, KCNQ1, POLR2F
Drugs: Dactinomycin, Doxorubicin, FLUORODOPA F 18