Familial hyperinsulinism

Summary

Familial hyperinsulinism (MONDO:0017182) is a disease caused by ABCC8 (GenCC Definitive), with 6 cohort genes and 35 clinical trials. Top therapeutic interventions include fluorodopa f 18, pasireotide, and acarbose.

At a glance

• Causal gene: ABCC8 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 205
• Clinical trials: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperinsulinism
Mondo ID	MONDO:0017182
Orphanet	276525
NCIT	C131425
UMLS	C3888018
MedGen	854723
GARD	0021053
Is cancer (heuristic)	no

Also known as: congenital hyperinsulinism · familial hyperinsulinemic hypoglycemia · FHI · hereditary hyperinsulinism (disease) · HHI · hyperinsulinemia of infancy · hyperinsulinemic hypoglycemia · neonatal hyperinsulinism · nesidioblastosis

Data availability: 205 ClinVar variants · 1 GenCC gene-disease record · 8 cell lines.

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 › hyperinsulinism › familial hyperinsulinism

Subtypes (3): hyperinsulinism due to INSR deficiency, adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia, congenital isolated hyperinsulinism

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

205 retrieved; paginated sample, class counts are floors:

87 conflicting classifications of pathogenicity, 34 pathogenic/likely pathogenic, 25 benign/likely benign, 23 pathogenic, 11 benign, 10 likely pathogenic, 10 uncertain significance, 3 likely benign, 2 uncertain significance/uncertain 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
1075098	NM_000352.6(ABCC8):c.3000C>A (p.Cys1000Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098777	NM_000352.6(ABCC8):c.4288del (p.Leu1430fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338454	NM_000352.6(ABCC8):c.4252C>T (p.Arg1418Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338676	NM_000352.6(ABCC8):c.805del (p.Ala269fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459964	NM_000352.6(ABCC8):c.502C>T (p.Arg168Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526017	NM_000352.6(ABCC8):c.1330C>T (p.Gln444Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
157696	NM_000352.6(ABCC8):c.3509del (p.Leu1170fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1878337	NM_000352.6(ABCC8):c.1630+1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188905	NM_000352.6(ABCC8):c.2857C>T (p.Gln953Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188931	NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)	ABCC8	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
210074	NM_000352.6(ABCC8):c.331G>A (p.Gly111Arg)	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
2137006	NM_000352.6(ABCC8):c.4532T>C (p.Ile1511Thr)	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
235633	NM_000352.6(ABCC8):c.3640C>T (p.Arg1214Trp)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
2678076	NM_000352.6(ABCC8):c.96C>G (p.Asn32Lys)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
3233511	NC_000011.9:g.(17453792_17464266)_(17464860_17470062)del	ABCC8	Pathogenic	criteria provided, single submitter
3233553	NM_000352.6(ABCC8):c.4432G>C (p.Gly1478Arg)	ABCC8	Pathogenic	criteria provided, single submitter
35616	NM_000352.6(ABCC8):c.4198G>A (p.Gly1400Arg)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370163	NM_000352.6(ABCC8):c.3748C>T (p.Arg1250Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
370210	NM_000352.6(ABCC8):c.3574del (p.Asp1192fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
370935	NM_000352.6(ABCC8):c.3400-1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371380	NM_000352.6(ABCC8):c.220C>T (p.Arg74Trp)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3721002	NM_000352.6(ABCC8):c.4474G>A (p.Ala1492Thr)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434048	NM_000352.6(ABCC8):c.2921-9G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434055	NM_000352.6(ABCC8):c.1254_1284dup (p.Met429Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
434056	NM_000352.6(ABCC8):c.1792C>T (p.Arg598Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
446765	NM_000352.6(ABCC8):c.1634del (p.Phe545fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 23 · 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	Autosomal recessive	familial hyperinsulinism	32

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
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
GLUD1	Orphanet:35878	Hyperinsulinism-hyperammonemia syndrome
HADH	Orphanet:71212	Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY
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

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	clinvar
GLUD1	HGNC:4335	ENSG00000148672	P00367	Glutamate dehydrogenase 1, mitochondrial	clinvar
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	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.
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).
GLUD1	Glutamate dehydrogenase 1, mitochondrial	Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate.
HADH	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).
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.
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: 6 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Nuclear receptor	1	64.3×	0.077
Ion channel	1	18.6×	0.104
Transporter	1	13.0×	0.104
Enzyme (other)	2	4.0×	0.104
Kinase	1	4.6×	0.198

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
GLUD1	Enzyme (other)	yes	1.4.1.3	Glu/Leu/Phe/Val/Trp_DH, Glu/Leu/Phe/Val/Trp_DH_C, Glu/Leu/Phe/Val/Trp_DH_dimer
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
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.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	3
right lobe of liver	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adenohypophysis	1
pituitary gland	1
nucleus accumbens	1
superior vestibular nucleus	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
duodenum	1
mucosa of transverse colon	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	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
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
GLUD1	291	ubiquitous	marker	right lobe of liver, nucleus accumbens, superior vestibular nucleus
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
GLUD1	3,309
ABCC8	2,826
HADH	2,386
GCK	2,245
KCNJ11	1,715

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
GCK	KCNJ11	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCK	P35557	35
HADH	Q16836	12
KCNJ11	Q14654	9
ABCC8	Q09428	8
HNF4A	P41235	8
GLUD1	P00367	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCC8 can cause hypo- and hyper-glycemias	2	1903.3×	8e-06	ABCC8, KCNJ11
ATP sensitive Potassium channels	2	951.7×	2e-05	ABCC8, KCNJ11
Inwardly rectifying K+ channels	2	237.9×	3e-04	ABCC8, KCNJ11
Regulation of gene expression in beta cells	2	173.0×	4e-04	GCK, HNF4A
ABC transporter disorders	2	146.4×	5e-04	ABCC8, KCNJ11
Regulation of insulin secretion	2	73.2×	0.002	ABCC8, KCNJ11
Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)	1	1903.3×	0.002	GCK
Integration of energy metabolism	2	58.6×	0.002	ABCC8, KCNJ11
Disorders of transmembrane transporters	2	46.4×	0.003	ABCC8, KCNJ11
Potassium Channels	2	44.8×	0.003	ABCC8, KCNJ11
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	951.7×	0.003	KCNJ11
Mitochondrial protein degradation	2	38.1×	0.003	GLUD1, HADH
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	380.7×	0.005	HADH
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	380.7×	0.005	HADH
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	380.7×	0.005	HADH
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	380.7×	0.005	HADH
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	317.2×	0.006	HADH
Nephron development	1	146.4×	0.012	HNF4A
Glutamate and glutamine metabolism	1	135.9×	0.012	GLUD1
Neuronal System	2	14.8×	0.012	ABCC8, KCNJ11
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	63.4×	0.024	GCK
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	59.5×	0.024	GCK
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	59.5×	0.024	GCK
Glycolysis	1	47.6×	0.029	GCK
Transcriptional activation of mitochondrial biogenesis	1	34.0×	0.036	GLUD1
Ion homeostasis	1	34.0×	0.036	KCNJ11
Nuclear Receptor transcription pathway	1	33.4×	0.036	HNF4A
ABC-family protein mediated transport	1	20.2×	0.057	KCNJ11
Cardiac conduction	1	18.1×	0.061	KCNJ11
Disease	2	4.4×	0.078	ABCC8, KCNJ11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 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	326.6×	5e-11	ABCC8, GCK, HADH, HNF4A, KCNJ11
negative regulation of insulin secretion	3	247.8×	7e-06	ABCC8, HADH, KCNJ11
obsolete inorganic cation transmembrane transport	2	312.1×	5e-04	ABCC8, KCNJ11
intracellular glucose homeostasis	2	193.7×	1e-03	ABCC8, GCK
cellular response to nutrient levels	2	156.0×	1e-03	ABCC8, KCNJ11
response to xenobiotic stimulus	3	34.5×	1e-03	ABCC8, HADH, KCNJ11
potassium ion import across plasma membrane	2	122.1×	0.001	ABCC8, KCNJ11
action potential	2	119.5×	0.001	ABCC8, KCNJ11
glucose metabolic process	2	85.1×	0.002	GCK, KCNJ11
response to glucose	2	85.1×	0.002	GCK, HNF4A
positive regulation of insulin secretion	2	85.1×	0.002	GCK, GLUD1
regulation of growth hormone receptor signaling pathway	1	2808.7×	0.002	HNF4A
negative regulation of neuroblast migration	1	2808.7×	0.002	ABCC8
obsolete regulation of ornithine metabolic process	1	2808.7×	0.002	HNF4A
positive regulation of uterine smooth muscle relaxation	1	2808.7×	0.002	ABCC8
response to insulin	2	77.0×	0.002	ABCC8, HADH
potassium ion transmembrane transport	2	45.3×	0.004	ABCC8, KCNJ11
glucose homeostasis	2	43.5×	0.004	GCK, HNF4A
glutamate secretion, neurotransmission	1	936.2×	0.005	ABCC8
negative regulation of blood-brain barrier permeability	1	936.2×	0.005	ABCC8
L-glutamate catabolic process	1	702.2×	0.006	GLUD1
obsolete glutamate biosynthetic process	1	561.7×	0.007	GLUD1
response to resveratrol	1	561.7×	0.007	KCNJ11
positive regulation of tight junction disassembly	1	561.7×	0.007	ABCC8
response to pH	1	468.1×	0.007	ABCC8
regulation of gastrulation	1	468.1×	0.007	HNF4A
CAMKK-AMPK signaling cascade	1	468.1×	0.007	KCNJ11
tricarboxylic acid metabolic process	1	468.1×	0.007	GLUD1
glucose catabolic process	1	401.2×	0.008	GCK
ventricular cardiac muscle tissue development	1	351.1×	0.008	KCNJ11

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 3

Druggability breadth: 5 of 6 evidence-associated genes (83%) 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
GLUD1	0	0
HADH	0	0
HNF4A	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
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): 3.

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

Symbol	Assays	Type breakdown
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
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase
GLUD1	1.4.1.3	glutamate dehydrogenase [NAD(P)+]
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

13 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
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	1	GCK
C	Druggable family + PDB, no drug	3	GLUD1, HADH, HNF4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF4A	106	—
GLUD1	0	—
HADH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 35.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	13
Not specified	8
PHASE3	5
PHASE1/PHASE2	3
PHASE1	3
PHASE4	1
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01070758	PHASE4	COMPLETED	Lanreotide Autogel Treatment of Patients With Congenital Hyperinsulinism of Infancy
NCT03941236	PHASE3	ACTIVE_NOT_RECRUITING	Extension Trial Evaluating the Long-term Safety and Efficacy of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT04706910	PHASE3	RECRUITING	18F-DOPA II - PET Imaging Optimization
NCT06208215	PHASE3	ACTIVE_NOT_RECRUITING	RZ358 Treatment for Congenital Hyperinsulinism
NCT03042416	PHASE3	COMPLETED	18F-DOPA PET Imaging: an Evaluation of Biodistribution and Safety
NCT03777176	PHASE3	COMPLETED	A Two-Period Open-label Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT04172441	PHASE2/PHASE3	COMPLETED	Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT04205604	PHASE2	RECRUITING	18FluoroLDOPA PET Imaging for the Detection and Localization of Focal Congenital Hyperinsulinism
NCT04732416	PHASE2	ACTIVE_NOT_RECRUITING	HM15136 (Efpegerglucagon) Treatment for 8 Weeks in Subjects Aged ≥2 Years With Congenital Hyperinsulinism (CHI)
NCT00571324	PHASE1/PHASE2	COMPLETED	Effect of Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism
NCT00674440	PHASE2	COMPLETED	Utility of [F-18] fluoroDOPA for Neonatal Hyperinsulinism
NCT00835328	PHASE1/PHASE2	TERMINATED	Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia
NCT00897676	PHASE1/PHASE2	COMPLETED	Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity
NCT00987168	PHASE2	COMPLETED	Sandostatine® LP and Hyperinsulinism
NCT01468454	PHASE2	COMPLETED	Phase II Safety and Efficacy Study of 18FDOPA PET-CT in Children With Hyperinsulinemic Hypoglycemia
NCT02604485	PHASE2	COMPLETED	A Single-Dose Open-Label Study of XOMA 358 in Subjects With Congenital Hyperinsulinism
NCT02937558	PHASE2	COMPLETED	CSI-Glucagon for Prevention of Hypoglycemia in Children With Congenital Hyperinsulinism
NCT03053284	PHASE2	WITHDRAWN	Pasireotide in Hyperinsulinemic Hypoglycemia
NCT03770637	PHASE2	COMPLETED	Glucagon Ready to Use (RTU) in Subjects With Hyperinsulinemic Hypoglycemia After Bariatric Surgery
NCT03984370	PHASE2	COMPLETED	Dasiglucagon in the Treatment of Postprandial Hypoglycaemia After Roux-en-Y Gastric Bypass
NCT04538989	PHASE2	COMPLETED	An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism
NCT04652479	PHASE2	COMPLETED	Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia
NCT04836273	PHASE2	COMPLETED	Treatment of Post-bariatric Hypoglycaemia
NCT02021604	PHASE1	RECRUITING	Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma
NCT02685852	PHASE1	COMPLETED	Evaluating Exenatide for the Treatment of Postprandial Hyperinsulinemic Hypoglycemia
NCT03103009	PHASE1	COMPLETED	Treatment Plan for an Individual Patient With Pasireotide for Hyperinsulinemic Hypoglycemia
NCT02560376	EARLY_PHASE1	UNKNOWN	68Ga-NOTA-exendin-4 PET/CT for the Localization of Insulinoma and Diagnosis of Nesidioblastosis
NCT01916148	Not specified	AVAILABLE	18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic Hypoglycemia
NCT01933490	Not specified	COMPLETED	Post-Gastric Bypass Hypoglycemia
NCT02533219	Not specified	NO_LONGER_AVAILABLE	Study of the Use of [18F]-DOPA in Hyperinsulinemic Hypoglycemia
NCT02835131	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of SOM230 for Hyperinsulinemic/Hypoglycemia
NCT03768518	Not specified	UNKNOWN	GLP-1 Receptor Expression in CHI
NCT03930368	Not specified	UNKNOWN	Application of Raw Corn Starch on Patients With Insulinoma
NCT05597475	Not specified	UNKNOWN	GLP1R-imaging in Post-RYGB Hypoglycemia
NCT07614139	Not specified	COMPLETED	Continuous Glucose Monitoring Alerts, Accuracy, and Patient Outcomes in Adults With Inherited Metabolic Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUORODOPA F 18	4	4
PASIREOTIDE	4	2
ACARBOSE	4	1
FUROSEMIDE	4	1
GLUCAGON	4	1
LANREOTIDE	4	1
DASIGLUCAGON	3	5
AVEXITIDE	3	2
ERSODETUG	3	1
EFPEGERGLUCAGON	2	1
CHEMBL4175452	0	1
CHEMBL4299399	0	1
CHEMBL4760828	0	1