Transient neonatal diabetes mellitus
diseaseOn this page
Also known as chromosome 6-associated transient diabetes mellitusdiabetes mellitus, 6q24-related transient neonataldiabetes mellitus, transient neonatalTNDMtransient neonatal diabetes mellitus (disease)
Summary
Transient neonatal diabetes mellitus (MONDO:0020525) is a disease caused by variants in ABCC8, GATA4, GCK, and 4 other genes, with 11 cohort genes and 2 clinical trials. The dominant Reactome pathway is Regulation of insulin secretion (4 cohort genes).
At a glance
- Causal genes: ABCC8 (GenCC Strong), GATA4 (GenCC Strong), GCK (GenCC Strong), HNF1B (GenCC Strong) (+3 more)
- Cohort genes: 11
- ClinVar variants: 467
- Clinical trials: 2
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | transient neonatal diabetes mellitus |
| Mondo ID | MONDO:0020525 |
| DOID | DOID:0060334 |
| ICD-11 | 1596856936 |
| NCIT | C114899 |
| SNOMED CT | 237603002 |
| UMLS | C0342273 |
| MedGen | 449530 |
| GARD | 0025170 |
| Is cancer (heuristic) | no |
Also known as: chromosome 6-associated transient diabetes mellitus · diabetes mellitus, 6q24-related transient neonatal · diabetes mellitus, transient neonatal · TNDM · transient neonatal diabetes mellitus · transient neonatal diabetes mellitus (disease)
Data availability: 467 ClinVar variants · 12 GenCC gene-disease records · 1 HPO phenotype.
Disease family
An umbrella term covering 3 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 › transient neonatal diabetes mellitus
Related subtypes (3): permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, neonatal diabetes mellitus with congenital hypothyroidism, permanent neonatal diabetes mellitus
Subtypes (3): diabetes mellitus, transient neonatal, 1, diabetes mellitus, transient neonatal, 2, diabetes mellitus, transient neonatal, 3
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
467 retrieved; paginated sample, class counts are floors:
288 conflicting classifications of pathogenicity, 157 uncertain significance, 9 benign/likely benign, 7 benign, 3 pathogenic, 2 likely benign, 1 likely risk allele
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 21203 | NM_000525.4(KCNJ11):c.964G>A (p.Glu322Lys) | 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 |
| 1679512 | NM_000525.4(KCNJ11):c.149G>T (p.Arg50Leu) | KCNJ11 | Likely risk allele | criteria provided, single submitter |
| 1067664 | NM_000352.6(ABCC8):c.148+2T>C | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1078817 | NM_000352.6(ABCC8):c.1269C>T (p.Ile423=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1106008 | NM_000352.6(ABCC8):c.3081G>A (p.Val1027=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1112025 | NM_000352.6(ABCC8):c.639G>A (p.Leu213=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1112579 | NM_000352.6(ABCC8):c.4368C>T (p.Ile1456=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1133548 | NM_000352.6(ABCC8):c.1767G>A (p.Pro589=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1135533 | NM_000352.6(ABCC8):c.2291+7C>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1177448 | NM_000352.6(ABCC8):c.2390+219T>C | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1177449 | NM_000352.6(ABCC8):c.2390+123C>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1177450 | NM_000352.6(ABCC8):c.2390+93C>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1177451 | NM_000352.6(ABCC8):c.2256-50T>C | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1177452 | NM_000352.6(ABCC8):c.4119+93G>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157681 | NM_000352.6(ABCC8):c.1158C>T (p.Asn386=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157685 | NM_000352.6(ABCC8):c.1926C>G (p.Pro642=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157692 | NM_000352.6(ABCC8):c.2538C>T (p.His846=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157693 | NM_000352.6(ABCC8):c.2556+22G>A | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157694 | NM_000352.6(ABCC8):c.2820+17A>G | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157697 | NM_000352.6(ABCC8):c.3612C>T (p.Ala1204=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157700 | NM_000352.6(ABCC8):c.4120-27T>C | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157702 | NM_000352.6(ABCC8):c.423G>A (p.Val141=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 157708 | NM_000352.6(ABCC8):c.823-8C>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1605682 | NM_000352.6(ABCC8):c.954G>C (p.Leu318=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1684039 | NM_000352.6(ABCC8):c.4307+13A>G | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1684260 | NM_000352.6(ABCC8):c.4090G>T (p.Val1364Phe) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1684493 | NM_000352.6(ABCC8):c.3681C>G (p.Leu1227=) | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1684494 | NM_000352.6(ABCC8):c.3558-7G>T | ABCC8 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 137 · Orphanet: 43 · 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 |
| ZFP57 | Definitive | Autosomal recessive | diabetes mellitus, transient neonatal, 1 | 7 |
| GATA4 | Strong | Autosomal dominant | pancreatic hypoplasia-diabetes-congenital heart disease syndrome | 15 |
| INS | Strong | Autosomal dominant | transient neonatal diabetes mellitus | 18 |
| SLC2A2 | Strong | Autosomal recessive | neonatal diabetes mellitus | 8 |
| PLAGL1 | Supportive | Autosomal dominant | transient neonatal diabetes mellitus |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| ZFP57 | Orphanet:99886 | Transient 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| PLAGL1 | Orphanet:96191 | Paternal uniparental disomy of chromosome 6 syndrome |
| PLAGL1 | Orphanet:99886 | Transient neonatal diabetes mellitus |
| CEL | Orphanet:552 | MODY |
| GLIS3 | Orphanet:79118 | Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome |
Cohort genes → proteins
11 cohort genes, 11 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 11 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| ZFP57 | HGNC:18791 | ENSG00000204644 | Q9NU63 | Zinc finger protein 57 homolog | gencc,clinvar |
| ABCC8 | HGNC:59 | ENSG00000006071 | Q09428 | ATP-binding cassette sub-family C member 8 | 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 |
| HNF1B | HGNC:11630 | ENSG00000275410 | P35680 | Hepatocyte nuclear factor 1-beta | gencc |
| GATA4 | HGNC:4173 | ENSG00000136574 | P43694 | Transcription factor GATA-4 | gencc |
| GCK | HGNC:4195 | ENSG00000106633 | P35557 | Hexokinase-4 | gencc |
| INS | HGNC:6081 | ENSG00000254647 | P01308 | Insulin | gencc |
| PLAGL1 | HGNC:9046 | ENSG00000118495 | Q9UM63 | Zinc finger protein PLAGL1 | gencc |
| CEL | HGNC:1848 | ENSG00000170835 | P19835 | Bile salt-activated lipase | clinvar |
| GLIS3 | HGNC:28510 | ENSG00000107249 | Q8NEA6 | Zinc finger protein GLIS3 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| ZFP57 | Zinc finger protein 57 homolog | Transcription regulator required to maintain maternal and paternal gene imprinting, a process by which gene expression is restricted in a parent of origin-specific manner by epigenetic modification of genomic DNA and chromatin, including D… |
| 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. |
| 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. |
| HNF1B | Hepatocyte nuclear factor 1-beta | Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'. |
| 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. |
| 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. |
| PLAGL1 | Zinc finger protein PLAGL1 | Acts as a transcriptional activator. |
| CEL | Bile salt-activated lipase | Catalyzes the hydrolysis of a wide range of substrates including cholesteryl esters, phospholipids, lysophospholipids, di- and tri-acylglycerols, and fatty acid esters of hydroxy fatty acids (FAHFAs). |
| GLIS3 | Zinc finger protein GLIS3 | Acts both as a repressor and an activator of transcription. |
Protein-family classification
Druggable: 5 · Difficult: 5 · Unknown: 1 · Druggable fraction: 0.45
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 | 14.2× | 0.025 |
| Transcription factor | 5 | 3.8× | 0.025 |
| Ion channel | 1 | 10.1× | 0.189 |
| Kinase | 1 | 2.5× | 0.499 |
| Enzyme (other) | 1 | 1.1× | 0.740 |
| Other/Unknown | 1 | 0.2× | 1.000 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| ZFP57 | Transcription factor | no | KRAB, Znf_C2H2_type, KRAB_dom_sf | |
| ABCC8 | Transporter | yes | ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd | |
| 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 | |
| HNF1B | Transcription factor | no | HD, HNF1b_C, HNF-1_N | |
| GATA4 | Transcription factor | no | Znf_GATA, GATA_N, Znf_NHR/GATA | |
| GCK | Kinase | yes | 2.7.1.1 | Hexokinase, Hexokinase_BS, Hexokinase_N |
| INS | Other/Unknown | no | Insulin, Insulin-like, Ins/IGF/rlx | |
| PLAGL1 | Transcription factor | no | Znf_C2H2_type, Znf_C2H2_sf | |
| CEL | Enzyme (other) | yes | 3.1.1.13 | CarbesteraseB, Carboxylesterase_B_CS, Carboxylesterase_B_AS |
| GLIS3 | Transcription factor | no | Znf_C2H2_type, Znf_C2H2_sf, GLI-like |
Expression context
Cohort genes with no expression data: 0.
9 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) | 11 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| islet of Langerhans | 3 |
| body of pancreas | 2 |
| type B pancreatic cell | 2 |
| C1 segment of cervical spinal cord | 1 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| primordial germ cell in gonad | 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 |
| adult mammalian kidney | 1 |
| kidney | 1 |
| metanephros cortex | 1 |
| duodenum | 1 |
| heart left ventricle | 1 |
| right atrium auricular region | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| ZFP57 | 112 | tissue_specific | yes | primordial germ cell in gonad, C1 segment of cervical spinal cord, male germ line stem cell (sensu Vertebrata) in testis |
| ABCC8 | 185 | broad | marker | islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere |
| KCNJ11 | 161 | broad | yes | gastrocnemius, hindlimb stylopod muscle, muscle of leg |
| SLC2A2 | 80 | tissue_specific | marker | right lobe of liver, liver, jejunal mucosa |
| HNF1B | 74 | broad | marker | metanephros cortex, adult mammalian kidney, kidney |
| GATA4 | 85 | broad | marker | right atrium auricular region, heart left ventricle, duodenum |
| 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 |
| PLAGL1 | 280 | ubiquitous | marker | adrenal tissue, skin of hip, placenta |
| CEL | 186 | tissue_specific | marker | body of pancreas, type B pancreatic cell, pancreas |
| GLIS3 | 213 | ubiquitous | marker | buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell |
Protein interactions among cohort
Intra-cohort edges: 15.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| INS | 11,670 |
| GATA4 | 4,994 |
| SLC2A2 | 2,839 |
| ABCC8 | 2,826 |
| GCK | 2,245 |
| GLIS3 | 1,717 |
| KCNJ11 | 1,715 |
| HNF1B | 1,660 |
| PLAGL1 | 1,346 |
| CEL | 1,233 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| ABCC8 | GCK | string_interaction |
| ABCC8 | GLIS3 | string_interaction |
| ABCC8 | INS | string_interaction |
| ABCC8 | KCNJ11 | biogrid_interaction, intact, string_interaction |
| ABCC8 | SLC2A2 | string_interaction |
| ABCC8 | ZFP57 | string_interaction |
| GCK | HNF1B | string_interaction |
| GCK | INS | string_interaction |
| GCK | KCNJ11 | string_interaction |
| GCK | SLC2A2 | string_interaction |
| GLIS3 | KCNJ11 | string_interaction |
| INS | KCNJ11 | string_interaction |
| INS | SLC2A2 | string_interaction |
| KCNJ11 | SLC2A2 | string_interaction |
| KCNJ11 | ZFP57 | string_interaction |
Structural data
PDB: 7 · 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 |
| CEL | P19835 | 7 |
| HNF1B | P35680 | 3 |
| GATA4 | P43694 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| SLC2A2 | P11168 | 86.56 |
| PLAGL1 | Q9UM63 | 57.65 |
| ZFP57 | Q9NU63 | 56.76 |
| GLIS3 | Q8NEA6 | 49.95 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 76. Enrichment computed across 11 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Regulation of insulin secretion | 4 | 97.6× | 4e-06 | ABCC8, KCNJ11, SLC2A2, INS |
| Defective ABCC8 can cause hypo- and hyper-glycemias | 2 | 1268.9× | 1e-05 | ABCC8, KCNJ11 |
| Regulation of gene expression in beta cells | 3 | 173.0× | 1e-05 | SLC2A2, GCK, INS |
| ATP sensitive Potassium channels | 2 | 634.4× | 5e-05 | ABCC8, KCNJ11 |
| Developmental Lineage of Pancreatic Acinar Cells | 3 | 100.2× | 5e-05 | HNF1B, CEL, GATA4 |
| Integration of energy metabolism | 3 | 58.6× | 2e-04 | ABCC8, KCNJ11, INS |
| Inwardly rectifying K+ channels | 2 | 158.6× | 7e-04 | ABCC8, KCNJ11 |
| Developmental Lineage of Multipotent Pancreatic Progenitor Cells | 2 | 133.6× | 9e-04 | HNF1B, GATA4 |
| ABC transporter disorders | 2 | 97.6× | 0.002 | ABCC8, KCNJ11 |
| FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes | 2 | 84.6× | 0.002 | GCK, INS |
| Developmental Lineage of Pancreatic Ductal Cells | 2 | 50.8× | 0.005 | HNF1B, GATA4 |
| Defective GCK causes maturity-onset diabetes of the young 2 (MODY2) | 1 | 1268.9× | 0.005 | GCK |
| Defective SLC2A2 causes Fanconi-Bickel syndrome (FBS) | 1 | 1268.9× | 0.005 | SLC2A2 |
| Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome | 1 | 634.4× | 0.009 | KCNJ11 |
| Disorders of transmembrane transporters | 2 | 30.9× | 0.009 | ABCC8, KCNJ11 |
| Potassium Channels | 2 | 29.9× | 0.009 | ABCC8, KCNJ11 |
| Intestinal hexose absorption | 1 | 423.0× | 0.011 | SLC2A2 |
| IRS activation | 1 | 253.8× | 0.016 | INS |
| Formation of lateral plate mesoderm | 1 | 253.8× | 0.016 | GATA4 |
| Digestion of dietary lipid | 1 | 181.3× | 0.021 | CEL |
| Regulation of gene expression in early pancreatic precursor cells | 1 | 158.6× | 0.023 | HNF1B |
| Signal attenuation | 1 | 115.3× | 0.030 | INS |
| Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) | 1 | 97.6× | 0.031 | GATA4 |
| Signaling by Insulin receptor | 1 | 97.6× | 0.031 | INS |
| Nephron development | 1 | 97.6× | 0.031 | HNF1B |
| YAP1- and WWTR1 (TAZ)-stimulated gene expression | 1 | 84.6× | 0.031 | GATA4 |
| Digestion and absorption | 1 | 84.6× | 0.031 | CEL |
| Regulation of beta-cell development | 1 | 79.3× | 0.031 | INS |
| Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells | 1 | 79.3× | 0.031 | HNF1B |
| Transcriptional regulation of testis differentiation | 1 | 79.3× | 0.031 | GATA4 |
GO biological processes 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.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| regulation of insulin secretion | 3 | 106.9× | 5e-04 | ABCC8, KCNJ11, GCK |
| glucose metabolic process | 3 | 69.6× | 9e-04 | KCNJ11, GCK, INS |
| positive regulation of glycogen biosynthetic process | 2 | 180.2× | 0.002 | GCK, INS |
| obsolete inorganic cation transmembrane transport | 2 | 170.2× | 0.002 | ABCC8, KCNJ11 |
| negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway | 2 | 170.2× | 0.002 | GATA4, INS |
| negative regulation of gluconeogenesis | 2 | 145.9× | 0.002 | GCK, INS |
| intracellular glucose homeostasis | 2 | 105.7× | 0.004 | ABCC8, GCK |
| negative regulation of insulin secretion | 2 | 90.1× | 0.005 | ABCC8, KCNJ11 |
| cellular response to nutrient levels | 2 | 85.1× | 0.005 | ABCC8, KCNJ11 |
| regulation of pronephros size | 1 | 1532.0× | 0.006 | HNF1B |
| pronephric nephron tubule development | 1 | 1532.0× | 0.006 | HNF1B |
| ureteric bud elongation | 1 | 1532.0× | 0.006 | HNF1B |
| obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis | 1 | 1532.0× | 0.006 | HNF1B |
| negative regulation of neuroblast migration | 1 | 1532.0× | 0.006 | ABCC8 |
| mesenchymal cell apoptotic process involved in metanephros development | 1 | 1532.0× | 0.006 | HNF1B |
| positive regulation of uterine smooth muscle relaxation | 1 | 1532.0× | 0.006 | ABCC8 |
| positive regulation of insulin secretion involved in cellular response to glucose stimulus | 2 | 68.1× | 0.006 | ABCC8, SLC2A2 |
| potassium ion import across plasma membrane | 2 | 66.6× | 0.006 | ABCC8, KCNJ11 |
| action potential | 2 | 65.2× | 0.006 | ABCC8, KCNJ11 |
| response to xenobiotic stimulus | 3 | 18.8× | 0.006 | ABCC8, KCNJ11, GATA4 |
| response to glucose | 2 | 46.4× | 0.007 | HNF1B, GCK |
| wound healing | 2 | 41.4× | 0.009 | GATA4, INS |
| atrial septum secundum morphogenesis | 1 | 766.0× | 0.009 | GATA4 |
| negative regulation of glycogen catabolic process | 1 | 766.0× | 0.009 | INS |
| hepatoblast differentiation | 1 | 766.0× | 0.009 | HNF1B |
| mesonephric duct formation | 1 | 766.0× | 0.009 | HNF1B |
| embryonic heart tube anterior/posterior pattern specification | 1 | 510.7× | 0.011 | GATA4 |
| positive regulation of nitric-oxide synthase activity | 1 | 510.7× | 0.011 | INS |
| glutamate secretion, neurotransmission | 1 | 510.7× | 0.011 | ABCC8 |
| regulation of branch elongation involved in ureteric bud branching | 1 | 510.7× | 0.011 | HNF1B |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 7
Druggability breadth: 7 of 11 evidence-associated genes (64%) 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 |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| KCNJ11 | 7 | 4 |
| ABCC8 | 6 | 4 |
| GCK | 5 | 2 |
| SLC2A2 | 1 | 3 |
| ZFP57 | 0 | 0 |
| HNF1B | 0 | 0 |
| GATA4 | 0 | 0 |
| INS | 0 | 0 |
| PLAGL1 | 0 | 0 |
| CEL | 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 |
| 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 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| 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 |
| CEL | 7 | Binding:7 |
| GATA4 | 5 | Binding:5 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| GCK | 2.7.1.1 | hexokinase |
| CEL | 3.1.1.13 | sterol esterase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| KCNJ11 | 102 |
| GCK | 228 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
14 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 |
| 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 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | ABCC8, KCNJ11 |
| B | Phased (≥1) drug, not yet approved | 2 | SLC2A2, GCK |
| C | Druggable family + PDB, no drug | 1 | CEL |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 6 | ZFP57, HNF1B, GATA4, INS, PLAGL1, GLIS3 |
Undrugged target profiles
7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| ZFP57 | 0 | — |
| HNF1B | 0 | — |
| GATA4 | 5 | — |
| INS | 8 | — |
| PLAGL1 | 0 | — |
| CEL | 7 | — |
| GLIS3 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 2.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 2 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03655223 | Not specified | ENROLLING_BY_INVITATION | Early Check: Expanded Screening in Newborns |
| NCT05945576 | Not specified | RECRUITING | IDMet (RaDiCo Cohort) (RaDiCo-IDMet) |