Congenital isolated hyperinsulinism

Summary

Congenital isolated hyperinsulinism (MONDO:0019010) is a disease with 1 cohort gene and 25 clinical trials. Top therapeutic interventions include fluorodopa f 18, furosemide, and glucagon.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 25

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3.67	Worldwide	Validated
Point prevalence	1-5 / 10 000	23.2	China	Validated
Prevalence at birth	1-9 / 100 000	2.24	Czech Republic	Validated
Prevalence at birth	1-9 / 100 000	5.25	Japan	Validated
Prevalence at birth	1-9 / 100 000	3.52	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	2	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	40	Saudi Arabia	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital isolated hyperinsulinism
Mondo ID	MONDO:0019010
Orphanet	657
NCIT	C122923
GARD	0003947
NORD	999
Is cancer (heuristic)	no

Also known as: chi · Congenital Hyperinsulinism · congenital hyperinsulinism · hyperinsulinemic hypoglycemia familial · hyperinsulinism congenital · hyperinsulinism familial with pancreatic nesidioblastosis · hypoglycemia hyperinsulinemic of infancy · persistent hyperinsulinemic hypoglycemia of infancy · PHHI

Data availability: 1 ClinVar variant · 15 cell lines.

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 › islet cell adenomatosis › congenital isolated hyperinsulinism

Subtypes (4): hyperinsulinemic hypoglycemia, familial, 2, hyperinsulinemic hypoglycemia, familial, 3, diazoxide-sensitive diffuse hyperinsulinism, diazoxide-resistant 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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
217847	NM_000352.6(ABCC8):c.72C>A (p.Asn24Lys)	ABCC8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	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.

Protein-family classification

Druggable: 1 · 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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
islet of Langerhans	1
right hemisphere of cerebellum	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCC8	2,826

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCC8	Q09428	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	5710.0×	0.002	ABCC8
ATP sensitive Potassium channels	1	2855.0×	0.002	ABCC8
Inwardly rectifying K+ channels	1	713.8×	0.005	ABCC8
ABC transporter disorders	1	439.2×	0.006	ABCC8
Regulation of insulin secretion	1	219.6×	0.010	ABCC8
Integration of energy metabolism	1	175.7×	0.010	ABCC8
Disorders of transmembrane transporters	1	139.3×	0.010	ABCC8
Potassium Channels	1	134.3×	0.010	ABCC8
Neuronal System	1	44.3×	0.028	ABCC8
Disease	1	13.1×	0.084	ABCC8
Metabolism	1	11.6×	0.086	ABCC8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of neuroblast migration	1	16852.0×	9e-04	ABCC8
positive regulation of uterine smooth muscle relaxation	1	16852.0×	9e-04	ABCC8
glutamate secretion, neurotransmission	1	5617.3×	0.001	ABCC8
negative regulation of blood-brain barrier permeability	1	5617.3×	0.001	ABCC8
positive regulation of tight junction disassembly	1	3370.4×	0.002	ABCC8
response to pH	1	2808.7×	0.002	ABCC8
positive regulation of potassium ion transport	1	2106.5×	0.002	ABCC8
negative regulation of glial cell proliferation	1	1685.2×	0.002	ABCC8
negative regulation of low-density lipoprotein particle clearance	1	1532.0×	0.002	ABCC8
obsolete inorganic cation transmembrane transport	1	936.2×	0.003	ABCC8
response to zinc ion	1	624.1×	0.004	ABCC8
intracellular glucose homeostasis	1	581.1×	0.004	ABCC8
neuromuscular process	1	526.6×	0.004	ABCC8
negative regulation of insulin secretion	1	495.6×	0.004	ABCC8
cellular response to nutrient levels	1	468.1×	0.004	ABCC8
regulation of insulin secretion	1	391.9×	0.004	ABCC8
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	ABCC8
potassium ion import across plasma membrane	1	366.4×	0.004	ABCC8
action potential	1	358.6×	0.004	ABCC8
visual learning	1	306.4×	0.005	ABCC8
response to insulin	1	230.8×	0.006	ABCC8
female pregnancy	1	210.7×	0.006	ABCC8
potassium ion transport	1	191.5×	0.007	ABCC8
memory	1	183.2×	0.007	ABCC8
negative regulation of angiogenesis	1	168.5×	0.007	ABCC8
transmembrane transport	1	168.5×	0.007	ABCC8
positive regulation of tumor necrosis factor production	1	153.2×	0.007	ABCC8
potassium ion transmembrane transport	1	135.9×	0.008	ABCC8
response to lipopolysaccharide	1	124.8×	0.008	ABCC8
response to xenobiotic stimulus	1	69.1×	0.014	ABCC8

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCC8	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ABCC8	84	Functional:52, Binding:32

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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
GLYBURIDE	4	ABCC8
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCC8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	9
PHASE3	5
Not specified	5
PHASE1/PHASE2	3
PHASE4	1
PHASE2/PHASE3	1
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
NCT04538989	PHASE2	COMPLETED	An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism
NCT02021604	PHASE1	RECRUITING	Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma
NCT01916148	Not specified	AVAILABLE	18F-L-Fluoro-DOPA PET/CT Scan Localization of Focal Pancreatic Lesions in Subjects With Hyperinsulinemic 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
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
FUROSEMIDE	4	1
GLUCAGON	4	1
LANREOTIDE	4	1
PASIREOTIDE	4	1
DASIGLUCAGON	3	3
AVEXITIDE	3	1
ERSODETUG	3	1
EFPEGERGLUCAGON	2	1
CHEMBL4175452	0	1