Neonatal diabetes mellitus

Summary

Neonatal diabetes mellitus (MONDO:0016391) is a disease caused by variants in ABCC8, BSCL2, EIF2B1, and 7 other genes, with 19 cohort genes. The dominant Reactome pathway is Regulation of gene expression in beta cells (5 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Italy) [Orphanet-validated]
• Causal genes: ABCC8 (GenCC Strong), BSCL2 (GenCC Strong), EIF2B1 (GenCC Strong), GATA4 (GenCC Strong) (+6 more)
• Cohort genes: 19
• ClinVar variants: 64

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.62	Austria	Validated
Prevalence at birth	1-9 / 100 000	1.1	Italy	Validated
Prevalence at birth	1-9 / 100 000	1.12	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.1	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal diabetes mellitus
Mondo ID	MONDO:0016391
Orphanet	224
DOID	DOID:11717
ICD-10-CM	P70.2
ICD-11	1217915084
NCIT	C99248
SNOMED CT	49817004
UMLS	C0158981
MedGen	57645
GARD	0018682
MedDRA	10028933
Is cancer (heuristic)	no

Also known as: congenital diabetes mellitus · diabetes mellitus syndrome in newborn infant · NDM

Data availability: 64 ClinVar variants · 14 GenCC gene-disease records.

Disease family

An umbrella term covering 4 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

Related subtypes (1): maturity-onset diabetes of the young

Subtypes (4): permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, neonatal diabetes mellitus with congenital hypothyroidism, transient neonatal diabetes mellitus, permanent neonatal diabetes mellitus

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

64 retrieved; paginated sample, class counts are floors:

17 likely pathogenic, 15 conflicting classifications of pathogenicity, 15 pathogenic/likely pathogenic, 10 pathogenic, 2 benign/likely benign, 1 likely pathogenic/likely risk allele, 1 uncertain significance, 1 pathogenic/likely risk allele, 1 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069205	NM_000352.6(ABCC8):c.1617T>A (p.Tyr539Ter)	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
210076	NM_000352.6(ABCC8):c.3544C>T (p.Arg1182Trp)	ABCC8	Pathogenic/Likely 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
280114	NM_000352.6(ABCC8):c.4308-2A>G	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35615	NM_000352.6(ABCC8):c.4136G>T (p.Arg1379Leu)	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
446765	NM_000352.6(ABCC8):c.1634del (p.Phe545fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
551208	NM_000352.6(ABCC8):c.4322del (p.Pro1441fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
552652	NM_000352.6(ABCC8):c.3868-1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555310	NM_000352.6(ABCC8):c.2202del (p.Ala736fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556981	NM_000352.6(ABCC8):c.2835_2838del (p.Arg946fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
558438	NM_000352.6(ABCC8):c.1347_1348del (p.Ile450fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
585343	NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585348	NM_000352.6(ABCC8):c.4613G>A (p.Arg1538Gln)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633027	NM_000352.6(ABCC8):c.695G>A (p.Trp232Ter)	ABCC8	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
996301	NM_000352.6(ABCC8):c.2521C>T (p.Arg841Ter)	ABCC8	Pathogenic	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
21114	NM_000207.3(INS):c.127T>G (p.Cys43Gly)	INS-IGF2	Pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
158682	NM_000525.4(KCNJ11):c.679G>A (p.Glu227Lys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36431	NM_000525.4(KCNJ11):c.149G>A (p.Arg50Gln)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8666	NM_000525.4(KCNJ11):c.602G>A (p.Arg201His)	KCNJ11	Pathogenic	criteria provided, multiple submitters, no conflicts
8667	NM_000525.4(KCNJ11):c.175G>A (p.Val59Met)	KCNJ11	Pathogenic	criteria provided, multiple submitters, no conflicts
8668	NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys)	KCNJ11	Pathogenic	criteria provided, multiple submitters, no conflicts
1526001	NM_000352.6(ABCC8):c.634G>T (p.Asp212Tyr)	ABCC8	Likely pathogenic	criteria provided, single submitter
1526002	NM_000352.6(ABCC8):c.643G>A (p.Val215Ile)	ABCC8	Likely pathogenic	criteria provided, single submitter
1526003	NM_000352.6(ABCC8):c.1608T>A (p.Phe536Leu)	ABCC8	Likely pathogenic	criteria provided, single submitter
1526006	NM_000352.6(ABCC8):c.4264T>A (p.Ser1422Thr)	ABCC8	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 117 · Orphanet: 55 · 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
GATA6	Definitive	Autosomal dominant	pancreatic hypoplasia-diabetes-congenital heart disease syndrome	16
BSCL2	Strong	Autosomal recessive	neonatal diabetes mellitus	16
EIF2B1	Strong	Autosomal dominant	neonatal diabetes mellitus	5
GATA4	Strong	Autosomal dominant	pancreatic hypoplasia-diabetes-congenital heart disease syndrome	15
IL2RA	Strong	Autosomal recessive	neonatal diabetes mellitus with congenital hypothyroidism	6
MNX1	Strong	Autosomal recessive	neonatal diabetes mellitus	8
NKX2-2	Strong	Autosomal recessive	neonatal diabetes mellitus	2
ONECUT1	Strong	Autosomal recessive	neonatal diabetes mellitus	2
SLC2A2	Strong	Autosomal recessive	neonatal diabetes mellitus	8
AGPAT2	Limited	Autosomal recessive	neonatal diabetes mellitus	5
CD274	Limited	Autosomal recessive	neonatal diabetes mellitus
TMEM167A	Limited	Autosomal recessive	neonatal diabetes mellitus

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SLC2A2	Orphanet:2088	Fanconi-Bickel syndrome
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
AGPAT2	Orphanet:696189	Congenital generalized lipodystrophy type 1
EIF2B1	Orphanet:157713	Congenital or early infantile CACH syndrome
EIF2B1	Orphanet:157716	Late infantile CACH syndrome
EIF2B1	Orphanet:157719	Juvenile or adult CACH syndrome
EIF2B1	Orphanet:99853	Ovarioleukodystrophy
EIF2B1	Orphanet:99854	Cree leukoencephalopathy
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
GATA4	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
GATA4	Orphanet:99103	Atrial septal defect, ostium secundum type
GATA6	Orphanet:2140	Congenital diaphragmatic hernia
GATA6	Orphanet:2255	Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
GATA6	Orphanet:3303	Tetralogy of Fallot
GATA6	Orphanet:334	Hereditary atrial fibrillation
GATA6	Orphanet:665044	Common arterial trunk with aortic dominance
GATA6	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
GATA6	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA6	Orphanet:99103	Atrial septal defect, ostium secundum type
MNX1	Orphanet:1552	Currarino syndrome
IL2RA	Orphanet:169100	Immunodeficiency due to CD25 deficiency
IL2RA	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RA	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent 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

Cohort genes → proteins

19 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
SLC2A2	HGNC:11006	ENSG00000163581	P11168	Solute carrier family 2, facilitated glucose transporter member 2	gencc
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	gencc
CD274	HGNC:17635	ENSG00000120217	Q9NZQ7	Programmed cell death 1 ligand 1	gencc
TMEM167A	HGNC:28330	ENSG00000174695	Q8TBQ9	Protein kish-A	gencc
AGPAT2	HGNC:325	ENSG00000169692	O15120	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	gencc
EIF2B1	HGNC:3257	ENSG00000111361	Q14232	Translation initiation factor eIF2B subunit alpha	gencc
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	gencc
GATA6	HGNC:4174	ENSG00000141448	Q92908	Transcription factor GATA-6	gencc
MNX1	HGNC:4979	ENSG00000130675	P50219	Motor neuron and pancreas homeobox protein 1	gencc
IL2RA	HGNC:6008	ENSG00000134460	P01589	Interleukin-2 receptor subunit alpha	gencc
NKX2-2	HGNC:7835	ENSG00000125820	O95096	Homeobox protein Nkx-2.2	gencc
ONECUT1	HGNC:8138	ENSG00000169856	Q9UBC0	Hepatocyte nuclear factor 6	gencc
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	clinvar
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	clinvar
PDX1	HGNC:6107	ENSG00000139515	P52945	Pancreas/duodenum homeobox protein 1	clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2	Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose.
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
CD274	Programmed cell death 1 ligand 1	Plays a critical role in induction and maintenance of immune tolerance to self.
TMEM167A	Protein kish-A	Involved in the early part of the secretory pathway.
AGPAT2	1-acyl-sn-glycerol-3-phosphate acyltransferase beta	Converts 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone.
EIF2B1	Translation initiation factor eIF2B subunit alpha	Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit.
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.
GATA6	Transcription factor GATA-6	Transcriptional activator.
MNX1	Motor neuron and pancreas homeobox protein 1	Transcription factor.
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.
NKX2-2	Homeobox protein Nkx-2.2	Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas.
ONECUT1	Hepatocyte nuclear factor 6	Transcriptional activator.
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.
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).
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.

Protein-family classification

Druggable: 8 · Difficult: 6 · Unknown: 5 · Druggable fraction: 0.42

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
Transporter	2	8.2×	0.097
Transcription factor	6	2.6×	0.097
Complement	1	14.1×	0.183
Ion channel	1	5.9×	0.315
Antibody/Immunoglobulin	1	1.5×	0.574
Kinase	1	1.5×	0.574
Enzyme (other)	2	1.3×	0.574
Other/Unknown	5	0.5×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
SLC2A2	Transporter	yes		Glc_transpt_2, Sugar/inositol_transpt, MFS_sugar_transport-like
BSCL2	Other/Unknown	no		Seipin
CD274	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
TMEM167A	Other/Unknown	no		Ksh1, KISH_domain
AGPAT2	Enzyme (other)	yes	2.3.1.51	Plipid/glycerol_acylTrfase, AGP_acyltrans
EIF2B1	Other/Unknown	no		IF-2B-related, NagB/RpiA_transferase-like, elF-2B_alpha_N
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
GATA6	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
MNX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
IL2RA	Complement	yes		Sushi_SCR_CCP_dom, IL-2_rcpt_alpha, Sushi/SCR/CCP_sf
NKX2-2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ONECUT1	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
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

Expression context

Cohort genes with no expression data: 0.

18 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)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	5
body of pancreas	5
right lobe of liver	3
pancreas	3
jejunal mucosa	2
pituitary gland	2
ileal mucosa	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
liver	1
primary visual cortex	1
superior frontal gyrus	1
cartilage tissue	1
lower lobe of lung	1
placenta	1
adrenal tissue	1
lateral nuclear group of thalamus	1
mucosa of transverse colon	1
monocyte	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
SLC2A2	80	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
CD274	208	ubiquitous	marker	cartilage tissue, placenta, lower lobe of lung
TMEM167A	256	ubiquitous	marker	adrenal tissue, lateral nuclear group of thalamus, ileal mucosa
AGPAT2	257	ubiquitous	marker	mucosa of transverse colon, ileal mucosa, right lobe of liver
EIF2B1	279	ubiquitous	marker	oocyte, secondary oocyte, monocyte
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum
GATA6	204	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, jejunal mucosa
MNX1	130	broad	marker	pancreatic ductal cell, body of pancreas, pancreas
IL2RA	153	broad	marker	lymph node, vermiform appendix, caecum
NKX2-2	100	tissue_specific	marker	inferior vagus X ganglion, subthalamic nucleus, medulla oblongata
ONECUT1	56	broad	marker	body of pancreas, right lobe of liver, gall bladder
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
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

Protein interactions among cohort

Intra-cohort edges: 17.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
CD274	5,012
GATA4	4,994
PDHX	3,542
SLC2A2	2,839
ABCC8	2,826
IL2RA	2,557
EIF2B1	2,548
GCK	2,245
AGPAT2	2,048

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
AGPAT2	BSCL2	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	PDX1	string_interaction
GCK	SLC2A2	string_interaction
INS	KCNJ11	string_interaction
INS	PDX1	string_interaction
INS	SLC2A2	string_interaction
KCNJ11	PDX1	string_interaction
KCNJ11	SLC2A2	string_interaction
MNX1	SLC2A2	string_interaction
ONECUT1	PDX1	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
CD274	Q9NZQ7	76
GCK	P35557	35
EIF2B1	Q14232	27
IL2RA	P01589	10
KCNJ11	Q14654	9
ABCC8	Q09428	8
PDHX	O00330	5
INS-IGF2	F8WCM5	4
GATA4	P43694	3
PDX1	P52945	2
BSCL2	Q96G97	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGPAT2	O15120	91.66
SLC2A2	P11168	86.56
TMEM167A	Q8TBQ9	66.51
NKX2-2	O95096	64.62
ONECUT1	Q9UBC0	60.78
MNX1	P50219	59.46
GATA6	Q92908	53.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 92. Enrichment computed across 19 evidence-associated genes (15 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 15 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	5	173.0×	4e-09	SLC2A2, GCK, INS, PDX1, NKX2-2
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	4	160.3×	3e-07	GATA4, GATA6, PDX1, ONECUT1
Regulation of insulin secretion	4	58.6×	2e-05	ABCC8, SLC2A2, INS, KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	2	761.3×	4e-05	ABCC8, KCNJ11
ATP sensitive Potassium channels	2	380.7×	2e-04	ABCC8, KCNJ11
Developmental Lineage of Pancreatic Acinar Cells	3	60.1×	2e-04	GATA4, PDX1, ONECUT1
Developmental Lineage of Pancreatic Ductal Cells	3	45.7×	5e-04	GATA4, PDX1, ONECUT1
Regulation of gene expression in early pancreatic precursor cells	2	190.3×	5e-04	PDX1, ONECUT1
Integration of energy metabolism	3	35.1×	8e-04	ABCC8, INS, KCNJ11
Inwardly rectifying K+ channels	2	95.2×	0.002	ABCC8, KCNJ11
Formation of definitive endoderm	2	95.2×	0.002	GATA4, GATA6
ABC transporter disorders	2	58.6×	0.004	ABCC8, KCNJ11
Cardiogenesis	2	56.4×	0.004	GATA4, GATA6
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	50.8×	0.005	GCK, INS
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	761.3×	0.008	GCK
Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS)	1	761.3×	0.008	SLC2A2
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	380.7×	0.014	KCNJ11
Intestinal hexose absorption	1	253.8×	0.020	SLC2A2
Disorders of transmembrane transporters	2	18.6×	0.024	ABCC8, KCNJ11
Potassium Channels	2	17.9×	0.025	ABCC8, KCNJ11
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	1	152.3×	0.026	NKX2-2
IRS activation	1	152.3×	0.026	INS
Formation of lateral plate mesoderm	1	152.3×	0.026	GATA4
PDH complex synthesizes acetyl-CoA from PYR	1	108.8×	0.035	PDHX
Recycling of eIF2:GDP	1	84.6×	0.042	EIF2B1
Regulation of PD-L1(CD274) translation	1	84.6×	0.042	CD274
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	76.1×	0.043	GATA6
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	76.1×	0.043	IL2RA
Signal attenuation	1	69.2×	0.044	INS
STAT3 nuclear events downstream of ALK signaling	1	69.2×	0.044	CD274

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucose metabolic process	5	70.9×	2e-06	GCK, INS, PDX1, KCNJ11, ONECUT1
type B pancreatic cell differentiation	3	351.1×	9e-06	GATA6, PDX1, ONECUT1
response to xenobiotic stimulus	6	23.0×	1e-05	ABCC8, AGPAT2, GATA4, GATA6, PDX1, KCNJ11
atrioventricular node development	2	312.1×	8e-04	GATA4, GATA6
regulation of insulin secretion	3	65.3×	8e-04	ABCC8, GCK, KCNJ11
positive regulation of insulin secretion involved in cellular response to glucose stimulus	3	62.4×	8e-04	ABCC8, SLC2A2, PDX1
pancreatic A cell differentiation	2	267.5×	1e-03	GATA6, ONECUT1
transdifferentiation	2	234.1×	1e-03	GATA4, PDX1
cell fate commitment	3	49.3×	1e-03	GATA4, GATA6, ONECUT1
response to glucose	3	42.6×	0.001	EIF2B1, GCK, NKX2-2
atrioventricular canal development	2	170.2×	0.001	GATA4, GATA6
intestinal epithelial cell differentiation	2	170.2×	0.001	GATA4, GATA6
liver development	3	37.0×	0.002	GATA6, PDX1, ONECUT1
positive regulation of glycogen biosynthetic process	2	110.1×	0.003	GCK, INS
obsolete inorganic cation transmembrane transport	2	104.0×	0.003	ABCC8, KCNJ11
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	2	104.0×	0.003	GATA4, INS
negative regulation of lipid catabolic process	2	93.6×	0.004	BSCL2, INS
negative regulation of gluconeogenesis	2	89.2×	0.004	GCK, INS
endoderm development	2	69.3×	0.006	GATA4, ONECUT1
oligodendrocyte development	2	66.9×	0.006	EIF2B1, NKX2-2
intracellular glucose homeostasis	2	64.6×	0.006	ABCC8, GCK
digestive tract development	2	58.5×	0.007	PDX1, NKX2-2
negative regulation of insulin secretion	2	55.1×	0.008	ABCC8, KCNJ11
cellular response to nutrient levels	2	52.0×	0.008	ABCC8, KCNJ11
regulation of T cell tolerance induction	1	936.2×	0.009	IL2RA
type B pancreatic cell fate commitment	1	936.2×	0.009	NKX2-2
negative regulation of transforming growth factor beta2 production	1	936.2×	0.009	GATA6
tube morphogenesis	1	936.2×	0.009	GATA6
ventral spinal cord interneuron fate determination	1	936.2×	0.009	NKX2-2
negative regulation of neuroblast migration	1	936.2×	0.009	ABCC8

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 14

Druggability breadth: 11 of 19 evidence-associated genes (58%) 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
CD274	MOCLOBEMIDE
KCNJ11	PINACIDIL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4
ABCC8	6	4
GCK	5	2
CD274	4	4
SLC2A2	1	3
BSCL2	0	0
TMEM167A	0	0
AGPAT2	0	0
EIF2B1	0	0
GATA4	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
MOCLOBEMIDE	4	CD274
PYRVINIUM	4	CD274
RIFABUTIN	4	CD274
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
QUERCETIN	3	SLC2A2
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, KCNJ11
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
EVIXAPODLIN	1	CD274

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
CD274	525	Binding:520, Functional:5
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
AGPAT2	6	Binding:6
GATA4	5	Binding:5
IL2RA	2	Binding:2
EIF2B1	1	Binding:1
PDHX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGPAT2	2.3.1.51	1-acylglycerol-3-phosphate O-acyltransferase
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
CD274	525
GCK	228
KCNJ11	102

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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
MOCLOBEMIDE	4	CD274
PYRVINIUM	4	CD274
RIFABUTIN	4	CD274
PINACIDIL ANHYDROUS	4	KCNJ11
PROPAFENONE	4	KCNJ11
QUERCETIN	3	SLC2A2
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, KCNJ11
PIRAGLIATIN	2	GCK
NERIGLIATIN	2	GCK
PF-04991532	2	GCK
AZD-1656	2	GCK
MK-0941 FREE BASE	2	GCK
EVIXAPODLIN	1	CD274

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	ABCC8, CD274, KCNJ11
B	Phased (≥1) drug, not yet approved	2	SLC2A2, GCK
C	Druggable family + PDB, no drug	2	IL2RA, PDHX
D	Druggable family + AlphaFold only, no drug	1	AGPAT2
E	Difficult family or no structure, no drug	11	BSCL2, TMEM167A, EIF2B1, GATA4, GATA6, MNX1, NKX2-2, ONECUT1, INS-IGF2, INS (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PDX1	0	GCK
BSCL2	0	—
TMEM167A	0	—
AGPAT2	6	—
EIF2B1	1	—
GATA4	5	—
GATA6	0	—
MNX1	0	—
IL2RA	2	—
NKX2-2	0	—
ONECUT1	0	—
PDHX	1	—
INS-IGF2	0	—
INS	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.