Permanent neonatal diabetes mellitus

disease

On this page

Also known as diabetes mellitus, permanent neonatalmonogenic diabetes of infancyPNDM

Summary

Permanent neonatal diabetes mellitus (MONDO:0100164) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in ABCC8, GATA4, HNF1B, and 6 other genes, with 14 cohort genes and 3 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (4 cohort genes).

At a glance

Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
Causal genes: ABCC8 (GenCC Strong), GATA4 (GenCC Strong), HNF1B (GenCC Strong), INS (GenCC Strong) (+5 more)
Umbrella term: 5 Mondo subtypes
Cohort genes: 14
ClinVar variants: 354
Phenotypes (HPO): 35
Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	United Kingdom	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Poland	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.46	Slovakia	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	United States	Validated
Prevalence at birth	1-5 / 10 000	18	Oman	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000857	Neonatal insulin-dependent diabetes mellitus	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001824	Weight loss	Very frequent (80-99%)
HP:0001944	Dehydration	Very frequent (80-99%)
HP:0003074	Hyperglycemia	Very frequent (80-99%)
HP:0003076	Glycosuria	Very frequent (80-99%)
HP:0006274	Reduced pancreatic beta cells	Very frequent (80-99%)
HP:0011106	Hypovolemia	Very frequent (80-99%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0002804	Arthrogryposis multiplex congenita	Frequent (30-79%)
HP:0002919	Ketonuria	Frequent (30-79%)
HP:0005487	Prominent metopic ridge	Frequent (30-79%)
HP:0005750	Contractures of the joints of the lower limbs	Frequent (30-79%)
HP:0012594	Microalbuminuria	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001488	Bilateral ptosis	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0000124	Renal tubular dysfunction	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0002186	Apraxia	Occasional (5-29%)
HP:0002594	Pancreatic hypoplasia	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0010935	Abnormality of the upper urinary tract	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	permanent neonatal diabetes mellitus
Mondo ID	MONDO:0100164
MeSH	C563425
OMIM	606176
Orphanet	99885
DOID	DOID:0060639
ICD-11	33655955
NCIT	C114902
SNOMED CT	609565001
UMLS	C1833104
MedGen	371484
GARD	0010457
Is cancer (heuristic)	no

Also known as: diabetes mellitus, permanent neonatal · monogenic diabetes of infancy · PNDM

Data availability: 354 ClinVar variants · 16 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › neonatal diabetes mellitus › permanent neonatal diabetes mellitus

Subtypes (5): DEND syndrome, diabetes mellitus, permanent neonatal 2, diabetes mellitus, permanent neonatal 3, diabetes mellitus, permanent neonatal 4, permanent neonatal diabetes mellitus 1

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

354 retrieved; paginated sample, class counts are floors:

153 conflicting classifications of pathogenicity, 74 uncertain significance, 24 benign/likely benign, 22 pathogenic/likely pathogenic, 22 pathogenic, 17 benign, 12 not provided, 10 likely pathogenic, 8 likely benign, 4 likely risk allele, 3 pathogenic/likely risk allele, 2 drug response, 2 uncertain significance/uncertain risk allele, 1 likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1338472	NM_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
188915	NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21169	NM_000352.6(ABCC8):c.631C>A (p.Gln211Lys)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
21170	NM_000352.6(ABCC8):c.674T>C (p.Leu225Pro)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384195	NC_000011.10:g.17445123_17455212del	ABCC8	Pathogenic	criteria provided, single submitter
35611	NM_000352.6(ABCC8):c.3545G>A (p.Arg1182Gln)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434045	NM_000352.6(ABCC8):c.4432G>A (p.Gly1478Arg)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434047	NM_000352.6(ABCC8):c.3593C>T (p.Pro1198Leu)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495834	NM_000352.6(ABCC8):c.221G>A (p.Arg74Gln)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9102	NM_000352.6(ABCC8):c.394T>C (p.Phe132Leu)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9103	NM_000352.6(ABCC8):c.638T>G (p.Leu213Arg)	ABCC8	Pathogenic	no assertion criteria provided
9104	NM_000352.6(ABCC8):c.4270A>G (p.Ile1424Val)	ABCC8	Pathogenic	no assertion criteria provided
9105	NM_000352.6(ABCC8):c.4135C>T (p.Arg1379Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9108	NM_000352.6(ABCC8):c.1144G>A (p.Glu382Lys)	ABCC8	Pathogenic	no assertion criteria provided
9111	NM_000352.6(ABCC8):c.257T>G (p.Val86Gly)	ABCC8	Pathogenic	no assertion criteria provided
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	GCK	Pathogenic	reviewed by expert panel
16141	NM_000162.5(GCK):c.629T>A (p.Met210Lys)	GCK	Pathogenic	reviewed by expert panel
21075	NM_000162.5(GCK):c.1019+2T>G	GCK	Pathogenic	reviewed by expert panel
21076	NM_000162.5(GCK):c.1133C>T (p.Ala378Val)	GCK	Pathogenic	reviewed by expert panel
21077	NM_000162.5(GCK):c.1190G>T (p.Arg397Leu)	GCK	Pathogenic	reviewed by expert panel
21078	NM_000162.5(GCK):c.790G>A (p.Gly264Ser)	GCK	Pathogenic	reviewed by expert panel
265175	NM_000162.5(GCK):c.766G>A (p.Glu256Lys)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
36200	NM_000162.5(GCK):c.1358C>T (p.Ser453Leu)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435306	NM_000162.5(GCK):c.667G>A (p.Gly223Ser)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
13388	NM_000207.3(INS):c.71C>A (p.Ala24Asp)	INS	Pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
21117	NM_000207.3(INS):c.265C>T (p.Arg89Cys)	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21122	NM_000207.3(INS):c.94G>A (p.Gly32Ser)	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431442	NM_000207.3(INS):c.-152C>A	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431443	NM_000207.3(INS):c.-152C>G	INS	Pathogenic	criteria provided, multiple submitters, no conflicts
21114	NM_000207.3(INS):c.127T>G (p.Cys43Gly)	INS-IGF2	Pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 193 · Orphanet: 53 · 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
ABCC8	Definitive	Semidominant	diabetes mellitus	32
GCK	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 2	18
HNF1B	Definitive	Autosomal dominant	renal cysts and diabetes syndrome	13
KCNJ11	Definitive	Autosomal dominant	diabetes mellitus, transient neonatal, 3	25
PDHX	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 4	18
PDX1	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 4	12
PTF1A	Definitive	Autosomal recessive	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	12
GATA4	Strong	Autosomal dominant	pancreatic hypoplasia-diabetes-congenital heart disease syndrome	15
INS	Strong	Autosomal dominant	transient neonatal diabetes mellitus	18
MNX1	Strong	Autosomal recessive	neonatal diabetes mellitus	8
NEUROG3	Strong	Autosomal recessive	permanent neonatal diabetes mellitus	5
SLC2A2	Strong	Autosomal recessive	neonatal diabetes mellitus	8
STAT3	Supportive	Autosomal dominant	permanent neonatal diabetes mellitus	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
PTF1A	Orphanet:2805	Partial pancreatic agenesis
PTF1A	Orphanet:65288	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus
INS	Orphanet:552	MODY
INS	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
PDX1	Orphanet:2805	Partial pancreatic agenesis
PDX1	Orphanet:552	MODY
PDX1	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:276580	Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:276603	Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:552	MODY
KCNJ11	Orphanet:79134	DEND syndrome
KCNJ11	Orphanet:79644	Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:99886	Transient neonatal diabetes mellitus
KCNJ11	Orphanet:99989	Intermediate DEND syndrome
SLC2A2	Orphanet:2088	Fanconi-Bickel syndrome
STAT3	Orphanet:2314	Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency
STAT3	Orphanet:438159	STAT3-related early-onset multisystem autoimmune disease
STAT3	Orphanet:512017	Chronic lymphoproliferative disorder of natural killer cells
STAT3	Orphanet:520	Acute promyelocytic leukemia
STAT3	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
STAT3	Orphanet:86872	T-cell large granular lymphocyte leukemia
STAT3	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
NEUROG3	Orphanet:83620	Enteric anendocrinosis
GATA4	Orphanet:251071	8p23.1 microdeletion syndrome
GATA4	Orphanet:251510	46,XY partial gonadal dysgenesis
GATA4	Orphanet:3303	Tetralogy of Fallot
GATA4	Orphanet:334	Hereditary atrial fibrillation
GATA4	Orphanet:576232	Partial atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia

Cohort genes → proteins

14 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	gencc,clinvar
PTF1A	HGNC:23734	ENSG00000168267	Q7RTS3	Pancreas transcription factor 1 subunit alpha	gencc,clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gencc,clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	gencc,clinvar
PDX1	HGNC:6107	ENSG00000139515	P52945	Pancreas/duodenum homeobox protein 1	gencc,clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	gencc,clinvar
SLC2A2	HGNC:11006	ENSG00000163581	P11168	Solute carrier family 2, facilitated glucose transporter member 2	gencc
STAT3	HGNC:11364	ENSG00000168610	P40763	Signal transducer and activator of transcription 3	gencc
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gencc
NEUROG3	HGNC:13806	ENSG00000122859	Q9Y4Z2	Neurogenin-3	gencc
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	gencc
MNX1	HGNC:4979	ENSG00000130675	P50219	Motor neuron and pancreas homeobox protein 1	gencc
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
PTF1A	Pancreas transcription factor 1 subunit alpha	Transcription factor implicated in the cell fate determination in various organs.
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
INS	Insulin	Insulin decreases blood glucose concentration.
PDX1	Pancreas/duodenum homeobox protein 1	Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription.
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.
SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2	Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose.
STAT3	Signal transducer and activator of transcription 3	Signal transducer and transcription activator that mediates cellular responses to interleukins, KITLG/SCF, LEP and other growth factors.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
NEUROG3	Neurogenin-3	Is a transcriptional regulator involved in the control of enteroendocrine cell differentiation.
GATA4	Transcription factor GATA-4	Transcriptional activator that binds to the consensus sequence 5’-AGATAG-3’ and plays a key role in cardiac development and function.
MNX1	Motor neuron and pancreas homeobox protein 1	Transcription factor.

Protein-family classification

Druggable: 5 · Difficult: 7 · Unknown: 2 · Druggable fraction: 0.36

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
Transcription factor	7	4.1×	0.004
Transporter	2	11.1×	0.041
Ion channel	1	8.0×	0.237
Kinase	1	2.0×	0.603
Enzyme (other)	1	0.9×	0.846
Other/Unknown	2	0.3×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
PTF1A	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
PDX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
SLC2A2	Transporter	yes		Glc_transpt_2, Sugar/inositol_transpt, MFS_sugar_transport-like
STAT3	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
NEUROG3	Transcription factor	no		bHLH_dom, Ngn3_bHLH, HLH_DNA-bd_sf
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
MNX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf

Expression context

Cohort genes with no expression data: 0.

12 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)	1
broad (>20)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	6
body of pancreas	5
pancreas	4
type B pancreatic cell	2
duodenum	2
biceps brachii	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
adenohypophysis	1
pituitary gland	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
jejunal mucosa	1
liver	1
right lobe of liver	1
lower lobe of lung	1
pericardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
PTF1A	96	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
PDX1	30	tissue_specific	marker	islet of Langerhans, pancreas, body of pancreas
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg
SLC2A2	80	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
STAT3	301	ubiquitous	marker	type B pancreatic cell, pericardium, lower lobe of lung
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
NEUROG3	46	tissue_specific	yes	mucosa of transverse colon, duodenum, Ammon’s horn
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum
MNX1	130	broad	marker	pancreatic ductal cell, body of pancreas, pancreas
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 26.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
STAT3	10,108
GATA4	4,994
PDHX	3,542
SLC2A2	2,839
ABCC8	2,826
GCK	2,245
NEUROG3	1,826
KCNJ11	1,715
HNF1B	1,660

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	INS	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
ABCC8	PDX1	string_interaction
ABCC8	SLC2A2	string_interaction
GCK	HNF1B	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	PDX1	string_interaction
GCK	SLC2A2	string_interaction
HNF1B	NEUROG3	string_interaction
HNF1B	PDX1	string_interaction
INS	KCNJ11	string_interaction
INS	NEUROG3	string_interaction
INS	PDX1	string_interaction
INS	PTF1A	string_interaction
INS	SLC2A2	string_interaction
KCNJ11	PDX1	string_interaction
KCNJ11	PTF1A	string_interaction
KCNJ11	SLC2A2	string_interaction
MNX1	NEUROG3	string_interaction
MNX1	PTF1A	string_interaction
MNX1	SLC2A2	string_interaction
NEUROG3	PDX1	string_interaction
NEUROG3	SLC2A2	string_interaction
PDX1	PTF1A	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
GCK	P35557	35
KCNJ11	Q14654	9
ABCC8	Q09428	8
STAT3	P40763	6
PDHX	O00330	5
INS-IGF2	F8WCM5	4
HNF1B	P35680	3
GATA4	P43694	3
PDX1	P52945	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC2A2	P11168	86.56
NEUROG3	Q9Y4Z2	70.55
PTF1A	Q7RTS3	61.81
MNX1	P50219	59.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 146. Enrichment computed across 14 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of gene expression in beta cells	4	173.0×	7e-07	GCK, INS, PDX1, SLC2A2
Regulation of gene expression in early pancreatic precursor cells	3	356.9×	2e-06	PTF1A, PDX1, HNF1B
Developmental Lineage of Pancreatic Acinar Cells	4	100.2×	2e-06	PTF1A, PDX1, HNF1B, GATA4
Regulation of insulin secretion	4	73.2×	7e-06	ABCC8, INS, KCNJ11, SLC2A2
Defective ABCC8 can cause hypo- and hyper-glycemias	2	951.7×	2e-05	ABCC8, KCNJ11
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	3	150.3×	2e-05	PDX1, HNF1B, GATA4
ATP sensitive Potassium channels	2	475.8×	1e-04	ABCC8, KCNJ11
Developmental Lineage of Pancreatic Ductal Cells	3	57.1×	3e-04	PDX1, HNF1B, GATA4
Integration of energy metabolism	3	43.9×	6e-04	ABCC8, INS, KCNJ11
Inwardly rectifying K+ channels	2	119.0×	0.002	ABCC8, KCNJ11
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	2	119.0×	0.002	HNF1B, NEUROG3
ABC transporter disorders	2	73.2×	0.004	ABCC8, KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	63.4×	0.005	GCK, INS
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	951.7×	0.010	GCK
Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)	1	951.7×	0.010	SLC2A2
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	475.8×	0.019	KCNJ11
Signalling to STAT3	1	317.2×	0.023	STAT3
MET activates STAT3	1	317.2×	0.023	STAT3
Intestinal hexose absorption	1	317.2×	0.023	SLC2A2
Disorders of transmembrane transporters	2	23.2×	0.023	ABCC8, KCNJ11
Potassium Channels	2	22.4×	0.024	ABCC8, KCNJ11
PTK6 Activates STAT3	1	237.9×	0.028	STAT3
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	1	190.3×	0.031	NEUROG3
IRS activation	1	190.3×	0.031	INS
Formation of lateral plate mesoderm	1	190.3×	0.031	GATA4
Signaling by PDGFR in disease	1	135.9×	0.040	STAT3
PDH complex synthesizes acetyl-CoA from PYR	1	135.9×	0.040	PDHX
Interleukin-6 family signaling	1	119.0×	0.043	STAT3
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	105.7×	0.043	STAT3
Interleukin-9 signaling	1	105.7×	0.043	STAT3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transdifferentiation	3	486.1×	6e-06	PDX1, NEUROG3, GATA4
glucose metabolic process	4	78.6×	2e-05	GCK, INS, PDX1, KCNJ11
regulation of insulin secretion	3	90.4×	4e-04	GCK, ABCC8, KCNJ11
positive regulation of insulin secretion involved in cellular response to glucose stimulus	3	86.4×	4e-04	ABCC8, PDX1, SLC2A2
exocrine pancreas development	2	259.3×	0.001	PTF1A, PDX1
cellular response to leptin stimulus	2	235.7×	0.001	GCK, STAT3
response to xenobiotic stimulus	4	21.2×	0.001	ABCC8, PDX1, KCNJ11, GATA4
hindbrain development	2	172.8×	0.002	HNF1B, NEUROG3
positive regulation of glycogen biosynthetic process	2	152.5×	0.002	GCK, INS
endocrine pancreas development	2	144.0×	0.002	HNF1B, MNX1
obsolete inorganic cation transmembrane transport	2	144.0×	0.002	ABCC8, KCNJ11
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	2	144.0×	0.002	INS, GATA4
negative regulation of gluconeogenesis	2	123.5×	0.002	GCK, INS
glucose homeostasis	3	30.1×	0.002	GCK, INS, STAT3
pancreas development	2	103.7×	0.003	PTF1A, HNF1B
intracellular glucose homeostasis	2	89.4×	0.004	GCK, ABCC8
positive regulation of vascular endothelial growth factor production	2	76.2×	0.005	STAT3, GATA4
negative regulation of insulin secretion	2	76.2×	0.005	ABCC8, KCNJ11
cellular response to nutrient levels	2	72.0×	0.005	ABCC8, KCNJ11
insulin secretion	2	66.5×	0.006	PDX1, HNF1B
acute-phase response	2	64.8×	0.006	INS, STAT3
negative regulation of transcription by RNA polymerase II	5	6.8×	0.007	PDX1, STAT3, HNF1B, NEUROG3, GATA4
potassium ion import across plasma membrane	2	56.4×	0.007	ABCC8, KCNJ11
action potential	2	55.2×	0.007	ABCC8, KCNJ11
regulation of DNA-templated transcription	4	9.7×	0.007	PTF1A, INS, STAT3, GATA4
regulation of pronephros size	1	1296.3×	0.007	HNF1B
pronephric nephron tubule development	1	1296.3×	0.007	HNF1B
ureteric bud elongation	1	1296.3×	0.007	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	1296.3×	0.007	HNF1B
negative regulation of neuroblast migration	1	1296.3×	0.007	ABCC8

Therapeutics

Drug target analysis

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

Druggability breadth: 8 of 14 evidence-associated genes (57%) 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
ABCC8	REPAGLINIDE
KCNJ11	PINACIDIL ANHYDROUS
STAT3	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
STAT3	18	4
KCNJ11	7	4
ABCC8	6	4
GCK	5	2
SLC2A2	1	3
PDHX	0	0
PTF1A	0	0
INS	0	0
PDX1	0	0
HNF1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8, KCNJ11
GLYBURIDE	4	ABCC8, KCNJ11
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
QUERCETIN	3	SLC2A2
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, KCNJ11
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1
GCK	228	Binding:226, ADMET:1, Functional:1
KCNJ11	102	Functional:59, Binding:43
ABCC8	84	Functional:52, Binding:32
SLC2A2	12	Binding:11, Functional:1
INS	8	Binding:7, ADMET:1
GATA4	5	Binding:5
PDHX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDHX	1.2.1.104	pyruvate dehydrogenase system
GCK	2.7.1.1	hexokinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
KCNJ11	102
STAT3	1,319

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; 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)
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8, KCNJ11
GLYBURIDE	4	ABCC8, KCNJ11
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
MOMELOTINIB	4	STAT3
NITAZOXANIDE	4	STAT3
NICLOSAMIDE	4	STAT3
DIGOXIN	4	STAT3
BARICITINIB	4	STAT3
DIGITOXIN	4	STAT3
DEUCRAVACITINIB	4	STAT3
QUERCETIN	3	SLC2A2
CURCUMIN	3	STAT3
BARDOXOLONE METHYL	3	STAT3
NIFUROXAZIDE	3	STAT3
DELGOCITINIB	3	STAT3
LESTAURTINIB	3	STAT3
NAPABUCASIN	3	STAT3
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, KCNJ11
LEVOMENOL	2	STAT3
AZD-1480	2	STAT3
WP 1066	2	STAT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	ABCC8, KCNJ11, STAT3
B	Phased (≥1) drug, not yet approved	2	GCK, SLC2A2
C	Druggable family + PDB, no drug	1	PDHX
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	PTF1A, INS, PDX1, HNF1B, NEUROG3, GATA4, MNX1, INS-IGF2

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)
PDX1	0	GCK
PDHX	1	—
PTF1A	0	—
INS	8	—
HNF1B	0	—
NEUROG3	0	—
GATA4	5	—
MNX1	0	—
INS-IGF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02624817	PHASE4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	PHASE4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Cohort genes: PDHX, PTF1A, GCK, ABCC8, INS, PDX1, KCNJ11, SLC2A2, STAT3, HNF1B, NEUROG3, GATA4, MNX1