Maturity-onset diabetes of the young

disease

On this page

Also known as Mason type diabetesmaturity onset diabetes of the youngmaturity-onset diabetes of the young (disease)MODY

Summary

Maturity-onset diabetes of the young (MONDO:0018911) is a disease (an umbrella term covering 15 Mondo subtypes) caused by ABCC8 (GenCC Strong), with 19 cohort genes and 16 clinical trials. The dominant Reactome pathway is Regulation of gene expression in beta cells (6 cohort genes). Top therapeutic interventions include glimepiride.

At a glance

Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
Causal gene: ABCC8 (GenCC Strong)
Umbrella term: 15 Mondo subtypes
Cohort genes: 19
ClinVar variants: 2,003
Phenotypes (HPO): 27
Clinical trials: 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated
Point prevalence	1-5 / 10 000	10	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001952	Glucose intolerance	Frequent (30-79%)
HP:0003074	Hyperglycemia	Frequent (30-79%)
HP:0003076	Glycosuria	Frequent (30-79%)
HP:0004924	Abnormal oral glucose tolerance	Frequent (30-79%)
HP:0030794	Abnormal C-peptide level	Frequent (30-79%)
HP:0040214	Abnormal circulating insulin concentration	Frequent (30-79%)
HP:0040216	Hypoinsulinemia	Frequent (30-79%)
HP:0040217	Elevated hemoglobin A1c	Frequent (30-79%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000825	Hyperinsulinemic hypoglycemia	Occasional (5-29%)
HP:0000831	Insulin-resistant diabetes mellitus	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001520	Large for gestational age	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0008255	Transient neonatal diabetes mellitus	Occasional (5-29%)
HP:0025502	Overweight	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Excluded (0%)
HP:0001953	Diabetic ketoacidosis	Excluded (0%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)
HP:0000077	Abnormality of the kidney	Very rare (<1-4%)
HP:0000107	Renal cyst	Very rare (<1-4%)
HP:0000119	Abnormality of the genitourinary system	Very rare (<1-4%)
HP:0001513	Obesity	Very rare (<1-4%)
HP:0001738	Exocrine pancreatic insufficiency	Very rare (<1-4%)
HP:0002594	Pancreatic hypoplasia	Very rare (<1-4%)
HP:0012028	Hepatocellular adenoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	maturity-onset diabetes of the young
Mondo ID	MONDO:0018911
MeSH	C562772
OMIM	125850, 606391
Orphanet	552
DOID	DOID:0050524
NCIT	C114769
SNOMED CT	609561005
UMLS	C0342276
MedGen	87433
GARD	0003697
Is cancer (heuristic)	no

Also known as: Mason type diabetes · maturity onset diabetes of the young · maturity-onset diabetes of the young · maturity-onset diabetes of the young (disease) · MODY

Data availability: 2,003 ClinVar variants · 14 GenCC gene-disease records · 1 HPO phenotype · 136 cell lines.

Disease family

An umbrella term covering 15 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 › maturity-onset diabetes of the young

Related subtypes (1): 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

600 retrieved; paginated sample, class counts are floors:

148 uncertain significance, 147 conflicting classifications of pathogenicity, 81 pathogenic, 70 likely benign, 44 likely pathogenic, 35 benign/likely benign, 35 benign, 21 pathogenic/likely pathogenic, 7 uncertain risk allele, 6 likely risk allele, 5 uncertain significance/uncertain risk allele, 1 likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069205	NM_000352.6(ABCC8):c.1617T>A (p.Tyr539Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1506182	NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
196880	NM_000352.6(ABCC8):c.4160_4162del (p.Phe1387del)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
217846	NM_000352.6(ABCC8):c.683G>A (p.Gly228Asp)	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
1315998	NM_000545.8(HNF1A):c.1781G>T (p.Ser594Ile)	C12orf43	Pathogenic	reviewed by expert panel
1098819	NM_000162.5(GCK):c.1139A>C (p.His380Pro)	GCK	Pathogenic	reviewed by expert panel
1172896	NM_000162.5(GCK):c.660C>A (p.Cys220Ter)	GCK	Pathogenic	reviewed by expert panel
1200795	NM_000162.5(GCK):c.679+1G>A	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
129143	NM_000162.5(GCK):c.523G>A (p.Gly175Arg)	GCK	Pathogenic	reviewed by expert panel
129144	NM_000162.5(GCK):c.544G>A (p.Val182Met)	GCK	Pathogenic	reviewed by expert panel
129145	NM_000162.5(GCK):c.616A>C (p.Thr206Pro)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320655	NM_000162.5(GCK):c.1322C>G (p.Ser441Trp)	GCK	Pathogenic	reviewed by expert panel
1343440	NM_000162.5(GCK):c.179C>T (p.Thr60Ile)	GCK	Pathogenic	reviewed by expert panel
1365679	NM_000162.5(GCK):c.1340_1368del (p.Arg447fs)	GCK	Pathogenic	reviewed by expert panel
1405403	NM_000162.5(GCK):c.1019G>A (p.Ser340Asn)	GCK	Pathogenic	reviewed by expert panel
1453774	NM_000162.5(GCK):c.867T>A (p.Tyr289Ter)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1464253	NM_000162.5(GCK):c.671T>C (p.Met224Thr)	GCK	Pathogenic	reviewed by expert panel
16133	NM_000162.5(GCK):c.556C>T (p.Arg186Ter)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
16134	NM_000162.5(GCK):c.683C>T (p.Thr228Met)	GCK	Pathogenic	reviewed by expert panel
16135	NM_000162.5(GCK):c.781G>A (p.Gly261Arg)	GCK	Pathogenic	reviewed by expert panel
1679552	NM_000162.5(GCK):c.208G>A (p.Glu70Lys)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683779	NM_000162.5(GCK):c.579G>T (p.Gly193=)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698944	NM_000162.5(GCK):c.641dup (p.Tyr214Ter)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700678	NM_000162.5(GCK):c.351_358del (p.Thr118fs)	GCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1731302	NM_000162.5(GCK):c.1141_1142del (p.Met381fs)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1735443	NM_000162.5(GCK):c.1156del (p.Leu386fs)	GCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1740762	NM_000162.5(GCK):c.445dup (p.Thr149fs)	GCK	Pathogenic	criteria provided, single submitter
1741488	NM_000162.5(GCK):c.455T>C (p.Phe152Ser)	GCK	Pathogenic	reviewed by expert panel
1743101	NM_000162.5(GCK):c.478G>C (p.Asp160His)	GCK	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 177 · Orphanet: 70 · 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
HNF1A	Definitive	Autosomal dominant	monogenic diabetes	11
HNF4A	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 1	11
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
APPL1	Strong	Autosomal dominant	maturity-onset diabetes of the young type 14	5
CEL	Strong	Autosomal dominant	maturity-onset diabetes of the young type 8	5
INS	Strong	Autosomal dominant	transient neonatal diabetes mellitus	18
KLF11	Strong	Autosomal dominant	maturity-onset diabetes of the young type 7	3
NEUROD1	Strong	Autosomal recessive	permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	10
BLK	Supportive	Autosomal dominant	maturity-onset diabetes of the young	5
PAX4	Supportive	Autosomal dominant	maturity-onset diabetes of the young	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
KLF11	Orphanet:552	MODY
CEL	Orphanet:552	MODY
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
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY
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
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
NEUROD1	Orphanet:552	MODY
PAX4	Orphanet:552	MODY
BLK	Orphanet:536	Systemic lupus erythematosus
BLK	Orphanet:552	MODY
APPL1	Orphanet:552	MODY
INS	Orphanet:552	MODY
INS	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
PTF1A	Orphanet:2805	Partial pancreatic agenesis
PTF1A	Orphanet:65288	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy

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
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gencc,clinvar
KLF11	HGNC:11811	ENSG00000172059	O14901	Krueppel-like factor 11	gencc,clinvar
CEL	HGNC:1848	ENSG00000170835	P19835	Bile salt-activated lipase	gencc,clinvar
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	gencc,clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gencc,clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	gencc,clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	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
NEUROD1	HGNC:7762	ENSG00000162992	Q13562	Neurogenic differentiation factor 1	gencc,clinvar
PAX4	HGNC:8618	ENSG00000106331	O43316	Paired box protein Pax-4	gencc,clinvar
BLK	HGNC:1057	ENSG00000136573	P51451	Tyrosine-protein kinase Blk	gencc
APPL1	HGNC:24035	ENSG00000157500	Q9UKG1	DCC-interacting protein 13-alpha	gencc
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	gencc
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	clinvar
EDEM2	HGNC:15877	ENSG00000088298	Q9BV94	ER degradation-enhancing alpha-mannosidase-like protein 2	clinvar
PTF1A	HGNC:23734	ENSG00000168267	Q7RTS3	Pancreas transcription factor 1 subunit alpha	clinvar
C12orf43	HGNC:25719	ENSG00000157895	Q96C57	Protein CUSTOS	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
KLF11	Krueppel-like factor 11	Transcription factor.
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).
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).
HNF4A	Hepatocyte nuclear factor 4-alpha	Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes.
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.
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.
NEUROD1	Neurogenic differentiation factor 1	Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5’-CANNTG-3'.
PAX4	Paired box protein Pax-4	Plays an important role in the differentiation and development of pancreatic islet beta cells.
BLK	Tyrosine-protein kinase Blk	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling.
APPL1	DCC-interacting protein 13-alpha	Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism.
INS	Insulin	Insulin decreases blood glucose concentration.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
EDEM2	ER degradation-enhancing alpha-mannosidase-like protein 2	Involved in the endoplasmic reticulum-associated degradation (ERAD) pathway that targets misfolded glycoproteins for degradation in an N-glycan-dependent manner.
PTF1A	Pancreas transcription factor 1 subunit alpha	Transcription factor implicated in the cell fate determination in various organs.
C12orf43	Protein CUSTOS	Plays a role in the regulation of Wnt signaling pathway during early development.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

Protein-family classification

Druggable: 7 · Difficult: 8 · Unknown: 4 · Druggable fraction: 0.37

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	3.0×	0.041
Nuclear receptor	1	20.3×	0.193
Ion channel	1	5.9×	0.315
Kinase	2	2.9×	0.315
Transporter	1	4.1×	0.349
Enzyme (other)	2	1.3×	0.638
Scaffold/PPI	1	0.9×	0.775
Other/Unknown	4	0.4×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
KLF11	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
CEL	Enzyme (other)	yes	3.1.1.13	CarbesteraseB, Carboxylesterase_B_CS, Carboxylesterase_B_AS
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
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
NEUROD1	Transcription factor	no		bHLH_dom, TF_bHLH_NeuroD, NeuroD_DUF
PAX4	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
BLK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
APPL1	Scaffold/PPI	no		PH_domain, BAR_dom, PTB/PI_dom
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
EDEM2	Other/Unknown	no		Glyco_hydro_47, 6hp_glycosidase-like_sf, Seven-hairpin_glycosidases
PTF1A	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
C12orf43	Other/Unknown	no		CUSTOS
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

Expression context

Cohort genes with no expression data: 0.

16 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	5
body of pancreas	4
pancreas	3
mucosa of transverse colon	2
right lobe of liver	2
oocyte	2
secondary oocyte	2
type B pancreatic cell	2
biceps brachii	2
cerebellar vermis	2
male germ line stem cell (sensu Vertebrata) in testis	2
liver	1
primordial germ cell in gonad	1
heart right ventricle	1
skeletal muscle tissue of biceps brachii	1
adenohypophysis	1
pituitary gland	1
duodenum	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
KLF11	260	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
CEL	186	tissue_specific	marker	body of pancreas, type B pancreatic cell, pancreas
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
PDX1	30	tissue_specific	marker	islet of Langerhans, pancreas, body of pancreas
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg
NEUROD1	115	broad	marker	paraflocculus, cerebellar vermis, cerebellum
PAX4	32	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, cerebellar vermis, Brodmann (1909) area 10
BLK	145	tissue_specific	marker	spleen, male germ line stem cell (sensu Vertebrata) in testis, lymph node
APPL1	284	ubiquitous	marker	calcaneal tendon, biceps brachii, germinal epithelium of ovary
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
EDEM2	241	ubiquitous	marker	granulocyte, monocyte, leukocyte
PTF1A	96	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
C12orf43	266	ubiquitous	marker	secondary oocyte, oocyte, prefrontal cortex
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 48.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
LMNA	7,173
HNF4A	4,731
PDHX	3,542
BLK	2,967
NEUROD1	2,901
ABCC8	2,826
APPL1	2,806
HNF1A	2,491
GCK	2,245

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	HNF1A	string_interaction
ABCC8	INS	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
ABCC8	KLF11	string_interaction
ABCC8	PAX4	string_interaction
ABCC8	PDX1	string_interaction
APPL1	KLF11	string_interaction
BLK	HNF1A	string_interaction
BLK	KLF11	string_interaction
BLK	NEUROD1	string_interaction
BLK	PAX4	string_interaction
GCK	HNF1A	string_interaction
GCK	HNF1B	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	KLF11	string_interaction
GCK	PDX1	string_interaction
HNF1A	HNF1B	biogrid_interaction, intact, string_interaction
HNF1A	HNF4A	string_interaction
HNF1A	INS	string_interaction
HNF1A	KCNJ11	string_interaction
HNF1A	KLF11	string_interaction
HNF1A	NEUROD1	string_interaction
HNF1A	PAX4	string_interaction
HNF1A	PDX1	string_interaction
HNF1A	PTF1A	string_interaction
HNF1B	HNF4A	string_interaction
HNF1B	KLF11	string_interaction
HNF1B	NEUROD1	string_interaction
HNF1B	PAX4	string_interaction
HNF1B	PDX1	string_interaction
INS	KCNJ11	string_interaction
INS	KLF11	string_interaction
INS	NEUROD1	string_interaction
INS	PAX4	string_interaction
INS	PDX1	string_interaction
INS	PTF1A	string_interaction
KCNJ11	KLF11	string_interaction
KCNJ11	PDX1	string_interaction
KCNJ11	PTF1A	string_interaction
KLF11	NEUROD1	intact, string_interaction
KLF11	PAX4	string_interaction
KLF11	PDX1	string_interaction
NEUROD1	PAX4	string_interaction
NEUROD1	PDHX	biogrid_interaction
NEUROD1	PDX1	string_interaction
PDX1	PTF1A	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
GCK	P35557	35
LMNA	P02545	28
KCNJ11	Q14654	9
HNF4A	P41235	8
ABCC8	Q09428	8
APPL1	Q9UKG1	8
CEL	P19835	7
HNF1A	P20823	6
PDHX	O00330	5
HNF1B	P35680	3
PDX1	P52945	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EDEM2	Q9BV94	85.61
BLK	P51451	81.89
PAX4	O43316	70.35
C12orf43	Q96C57	64.08
NEUROD1	Q13562	62.39
PTF1A	Q7RTS3	61.81
KLF11	O14901	49.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 92. Enrichment computed across 19 evidence-associated genes (17 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 17 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	6	183.2×	3e-11	HNF1A, GCK, HNF4A, PDX1, NEUROD1, INS
Regulation of gene expression in early pancreatic precursor cells	3	251.9×	7e-06	PDX1, HNF1B, PTF1A
Developmental Lineage of Pancreatic Acinar Cells	4	70.7×	7e-06	CEL, PDX1, HNF1B, PTF1A
Defective ABCC8 can cause hypo- and hyper-glycemias	2	671.8×	5e-05	ABCC8, KCNJ11
ATP sensitive Potassium channels	2	335.9×	2e-04	ABCC8, KCNJ11
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	2	268.7×	3e-04	NEUROD1, PAX4
Regulation of insulin secretion	3	38.8×	8e-04	ABCC8, KCNJ11, INS
Integration of energy metabolism	3	31.0×	0.001	ABCC8, KCNJ11, INS
Nephron development	2	103.3×	0.002	HNF4A, HNF1B
Inwardly rectifying K+ channels	2	84.0×	0.002	ABCC8, KCNJ11
Regulation of beta-cell development	2	84.0×	0.002	NEUROD1, INS
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	2	70.7×	0.003	PDX1, HNF1B
ABC transporter disorders	2	51.7×	0.005	ABCC8, KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	2	44.8×	0.006	GCK, INS
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	671.8×	0.009	GCK
Developmental Lineage of Pancreatic Ductal Cells	2	26.9×	0.014	PDX1, HNF1B
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	335.9×	0.016	KCNJ11
Breakdown of the nuclear lamina	1	223.9×	0.023	LMNA
Disorders of transmembrane transporters	2	16.4×	0.031	ABCC8, KCNJ11
Potassium Channels	2	15.8×	0.032	ABCC8, KCNJ11
IRS activation	1	134.3×	0.033	INS
RUNX1 regulates transcription of genes involved in BCR signaling	1	112.0×	0.037	BLK
Digestion of dietary lipid	1	96.0×	0.040	CEL
PDH complex synthesizes acetyl-CoA from PYR	1	96.0×	0.040	PDHX
Caspase activation via Dependence Receptors in the absence of ligand	1	67.2×	0.054	APPL1
Signal attenuation	1	61.1×	0.058	INS
Signaling by Insulin receptor	1	51.7×	0.065	INS
Depolymerization of the Nuclear Lamina	1	44.8×	0.070	LMNA
Digestion and absorption	1	44.8×	0.070	CEL
Regulation of pyruvate dehydrogenase (PDH) complex	1	42.0×	0.070	PDHX

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 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	5	103.1×	3e-07	GCK, HNF4A, ABCC8, KCNJ11, NEUROD1
insulin secretion	4	91.0×	1e-05	HNF1A, PDX1, NEUROD1, HNF1B
glucose homeostasis	5	34.4×	2e-05	HNF1A, GCK, HNF4A, NEUROD1, INS
glucose metabolic process	4	53.8×	4e-05	GCK, PDX1, KCNJ11, INS
response to glucose	4	53.8×	4e-05	GCK, HNF4A, NEUROD1, HNF1B
positive regulation of insulin secretion	4	53.8×	4e-05	GCK, PDX1, NEUROD1, BLK
pancreas development	3	106.4×	1e-04	HNF1A, HNF1B, PTF1A
type B pancreatic cell differentiation	2	221.7×	0.001	PDX1, PAX4
negative regulation of type B pancreatic cell apoptotic process	2	221.7×	0.001	PDX1, NEUROD1
exocrine pancreas development	2	177.4×	0.001	PDX1, PTF1A
amacrine cell differentiation	2	161.3×	0.002	NEUROD1, PTF1A
transcription by RNA polymerase II	4	14.8×	0.003	HNF4A, PDX1, NEUROD1, PTF1A
positive regulation of glycogen biosynthetic process	2	104.3×	0.003	GCK, INS
endocrine pancreas development	2	98.5×	0.003	NEUROD1, HNF1B
obsolete inorganic cation transmembrane transport	2	98.5×	0.003	ABCC8, KCNJ11
negative regulation of gluconeogenesis	2	84.5×	0.004	GCK, INS
signal transduction involved in regulation of gene expression	2	73.9×	0.005	HNF4A, NEUROD1
sensory organ development	2	71.0×	0.005	NEUROD1, PAX4
regulation of protein localization to plasma membrane	2	68.2×	0.006	APPL1, INS
intracellular glucose homeostasis	2	61.2×	0.007	GCK, ABCC8
negative regulation of insulin secretion	2	52.2×	0.008	ABCC8, KCNJ11
regulation of transcription by RNA polymerase II	7	4.3×	0.008	HNF1A, KLF11, HNF4A, PDX1, PAX4, HNF1B, PTF1A
regulation of pronephros size	1	887.0×	0.009	HNF1B
pronephric nephron tubule development	1	887.0×	0.009	HNF1B
regulation of growth hormone receptor signaling pathway	1	887.0×	0.009	HNF4A
ureteric bud elongation	1	887.0×	0.009	HNF1B
regulation of intestinal epithelial structure maintenance	1	887.0×	0.009	NEUROD1
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	887.0×	0.009	HNF1B
negative regulation of neuroblast migration	1	887.0×	0.009	ABCC8
obsolete regulation of ornithine metabolic process	1	887.0×	0.009	HNF4A

Therapeutics

Drug target analysis

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

Druggability breadth: 10 of 19 evidence-associated genes (53%) 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
BLK	AFATINIB
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
BLK	62	4
KCNJ11	7	4
ABCC8	6	4
GCK	5	2
HNF1A	0	0
KLF11	0	0
CEL	0	0
PDHX	0	0
HNF4A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8, LMNA
DIAZOXIDE	4	ABCC8, KCNJ11, LMNA
GLYBURIDE	4	ABCC8, KCNJ11, LMNA
PINACIDIL ANHYDROUS	4	KCNJ11, LMNA
PROPAFENONE	4	KCNJ11, LMNA
AFATINIB	4	BLK
FEDRATINIB	4	BLK
AXITINIB	4	BLK
SORAFENIB	4	BLK
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK
SUNITINIB	4	BLK, LMNA
DASATINIB	4	BLK
ERLOTINIB	4	BLK, LMNA
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
BLK	483	Binding:477, ADMET:4, Functional:2
GCK	228	Binding:226, ADMET:1, Functional:1
HNF4A	106	Binding:97, Functional:9
KCNJ11	102	Functional:59, Binding:43
ABCC8	84	Functional:52, Binding:32
LMNA	12	Binding:9, Functional:3
INS	8	Binding:7, ADMET:1
CEL	7	Binding:7
HNF1A	1	Binding:1
PDHX	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CEL	3.1.1.13	sterol esterase
PDHX	1.2.1.104	pyruvate dehydrogenase system
GCK	2.7.1.1	hexokinase
BLK	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
HNF4A	106
KCNJ11	102
BLK	483

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

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, LMNA
DIAZOXIDE	4	ABCC8, KCNJ11, LMNA
GLYBURIDE	4	ABCC8, KCNJ11, LMNA
PINACIDIL ANHYDROUS	4	KCNJ11, LMNA
PROPAFENONE	4	KCNJ11, LMNA
AFATINIB	4	BLK
FEDRATINIB	4	BLK
AXITINIB	4	BLK
SORAFENIB	4	BLK
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK
BOSUTINIB	4	BLK
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK
NINTEDANIB	4	BLK
SUNITINIB	4	BLK, LMNA
DASATINIB	4	BLK
ERLOTINIB	4	BLK, LMNA
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	ABCC8, KCNJ11, BLK, LMNA
B	Phased (≥1) drug, not yet approved	1	GCK
C	Druggable family + PDB, no drug	3	CEL, PDHX, HNF4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	HNF1A, KLF11, PDX1, NEUROD1, PAX4, APPL1, INS, HNF1B, EDEM2, PTF1A (+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)
HNF1A	1	GCK
KLF11	0	BLK
PDX1	0	GCK
HNF4A	106	—
CEL	7	—
PDHX	1	—
NEUROD1	0	—
PAX4	0	—
APPL1	0	—
INS	8	—
HNF1B	0	—
EDEM2	0	—
PTF1A	0	—
C12orf43	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE2/PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01610934	PHASE2/PHASE3	COMPLETED	The Effects of GLP-1 in Maturity-Onset Diabetes of The Young (MODY)
NCT07029009	PHASE2	RECRUITING	Liraglutide Treatment in Patients With Maturity-onset Diabetes of the Young (MODY)
NCT05586594	Not specified	NOT_YET_RECRUITING	Identifying Maturity-onset Diabetes of the Young in Emirati Patients
NCT06111833	Not specified	RECRUITING	Optimized Diagnosis and Precision Medicine of MODY
NCT06264427	Not specified	RECRUITING	Phenotypic and Genotypic Characterization of Patients With Dysmetabolism in Greenland
NCT07492004	Not specified	RECRUITING	China Monogenic Diabetes Registry
NCT01342939	Not specified	COMPLETED	Pathophysiological Implications of the Incretin Hormones in Maturity Onset of Diabetes of the Young (MODY)
NCT02082132	Not specified	UNKNOWN	MODY in Young-onset Diabetes in Different Ethnicities
NCT02556840	Not specified	COMPLETED	Impact on Birth Weight of Two Therapeutic Strategies (Insulin Therapy From the Beginning of Pregnancy vs. Insulin Therapy Initiated According to Fetal Growth Evaluated by Ultrasonography Measurements) in Pregnant Women With Monogenic Diabetes
NCT03589092	Not specified	UNKNOWN	Genetic Causes of Gestational Diabetes in the Emirati Population
NCT03607604	Not specified	UNKNOWN	Application of UCPCR as a Testing Tool for Identification of MODY Patients in the UAE
NCT04021199	Not specified	COMPLETED	Screening for Genetic Forms of Diabetes in Convention of Care for Children and Adolescents With Diabetes (GENEPEDIAB)
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05747118	Not specified	COMPLETED	A Feasibility Study of a 12 Week Training Intervention With Patients With Type 2 Diabetes and MODY in Greenland
NCT05918484	Not specified	COMPLETED	Usefulness of Continuous Glucose Monitoring in MODY Diagnosis
NCT06273059	Not specified	UNKNOWN	Genomic Study of Young-Onset Diabetes Mellitus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GLIMEPIRIDE	4	1

Cohort genes: HNF1A, KLF11, CEL, PDHX, GCK, HNF4A, ABCC8, PDX1, KCNJ11, NEUROD1, PAX4, BLK, APPL1, INS, HNF1B, EDEM2, PTF1A, C12orf43, LMNA
Drugs: Glimepiride