Hyperinsulinemic hypoglycemia, familial, 2

Summary

Hyperinsulinemic hypoglycemia, familial, 2 (MONDO:0011153) is a disease caused by KCNJ11 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: KCNJ11 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 173
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinemic hypoglycemia, familial, 2
Mondo ID	MONDO:0011153
OMIM	601820
DOID	DOID:0070218
UMLS	C2931833
MedGen	419173
GARD	0009927
Is cancer (heuristic)	no

Also known as: HHF2 · hyperinsulinemic hypoglycemia (disease) caused by mutation in KCNJ11 · hyperinsulinemic hypoglycemia due to Kir6.2 deficiency · hyperinsulinemic hypoglycemia familial 2 · hyperinsulinemic hypoglycemia, familial, 2 · hyperinsulinemic hypoglycemia, familial, type 2 · KCNJ11 hyperinsulinemic hypoglycemia (disease)

Data availability: 173 ClinVar variants · 7 GenCC gene-disease records.

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 › islet cell adenomatosis › congenital isolated hyperinsulinism › hyperinsulinemic hypoglycemia, familial, 2

Related subtypes (3): hyperinsulinemic hypoglycemia, familial, 3, diazoxide-sensitive diffuse hyperinsulinism, diazoxide-resistant hyperinsulinism

Subtypes (3): autosomal dominant hyperinsulinism due to Kir6.2 deficiency, diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency, autosomal recessive hyperinsulinism due to Kir6.2 deficiency

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

173 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 56 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 6 likely pathogenic, 5 benign/likely benign, 3 likely benign, 2 likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1162197	NM_000525.4(KCNJ11):c.617G>A (p.Arg206His)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1219242	NM_000525.4(KCNJ11):c.101G>A (p.Arg34His)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435558	NM_000525.4(KCNJ11):c.406C>T (p.Arg136Cys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551187	NM_000525.4(KCNJ11):c.560C>T (p.Ala187Val)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557416	NM_000525.4(KCNJ11):c.100C>T (p.Arg34Cys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8683	NM_000525.4(KCNJ11):c.902G>A (p.Arg301His)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8686	NM_000525.4(KCNJ11):c.844G>A (p.Glu282Lys)	KCNJ11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211229	NM_000525.4(KCNJ11):c.866G>T (p.Gly289Val)	KCNJ11	Likely pathogenic	criteria provided, single submitter
2137001	NM_000525.4(KCNJ11):c.271T>C (p.Trp91Arg)	KCNJ11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3239673	NM_000525.4(KCNJ11):c.1090del (p.Ala364fs)	KCNJ11	Likely pathogenic	criteria provided, single submitter
3599274	NM_000525.4(KCNJ11):c.1030_1031del (p.Cys344fs)	KCNJ11	Likely pathogenic	criteria provided, single submitter
3907675	NM_000525.4(KCNJ11):c.100C>G (p.Arg34Gly)	KCNJ11	Likely pathogenic	criteria provided, single submitter
8675	NM_000525.4(KCNJ11):c.761C>T (p.Pro254Leu)	KCNJ11	Likely pathogenic	criteria provided, multiple submitters, no conflicts
551025	NM_000525.4(KCNJ11):c.970G>A (p.Gly324Arg)	KCNJ11	Likely risk allele	criteria provided, single submitter
556175	NM_000525.4(KCNJ11):c.617G>T (p.Arg206Leu)	KCNJ11	Likely risk allele	criteria provided, single submitter
1065989	NM_000525.4(KCNJ11):c.405dup (p.Arg136fs)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158671	NM_000525.4(KCNJ11):c.1089A>G (p.Ser363=)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158672	NM_000525.4(KCNJ11):c.1143G>A (p.Lys381=)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158673	NM_000525.4(KCNJ11):c.161G>A (p.Arg54His)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158681	NM_000525.4(KCNJ11):c.584G>A (p.Arg195His)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158684	NM_000525.4(KCNJ11):c.801C>G (p.Leu267=)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158685	NM_000525.4(KCNJ11):c.808C>G (p.Leu270Val)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211227	NM_000525.4(KCNJ11):c.843C>T (p.Leu281=)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211228	NM_000525.4(KCNJ11):c.866G>C (p.Gly289Ala)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211230	NM_000525.4(KCNJ11):c.881C>T (p.Thr294Met)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242910	NM_000525.4(KCNJ11):c.154C>T (p.Gln52Ter)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2501786	NM_000525.4(KCNJ11):c.112A>G (p.Lys38Glu)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
256362	NM_000525.4(KCNJ11):c.1095C>T (p.Arg365=)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285043	NM_000525.4(KCNJ11):c.80G>A (p.Arg27His)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303708	NM_000525.4(KCNJ11):c.*1197G>A	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 8 · 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
KCNJ11	Definitive	Autosomal recessive	hyperinsulinemic hypoglycemia, familial, 2	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

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
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNJ11	1,715

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNJ11	Q14654	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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 ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	5710.0×	0.001	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	5710.0×	0.001	KCNJ11
ATP sensitive Potassium channels	1	2855.0×	0.002	KCNJ11
Inwardly rectifying K+ channels	1	713.8×	0.006	KCNJ11
ABC transporter disorders	1	439.2×	0.008	KCNJ11
Regulation of insulin secretion	1	219.6×	0.012	KCNJ11
Ion homeostasis	1	203.9×	0.012	KCNJ11
Integration of energy metabolism	1	175.7×	0.012	KCNJ11
Disorders of transmembrane transporters	1	139.3×	0.013	KCNJ11
Potassium Channels	1	134.3×	0.013	KCNJ11
ABC-family protein mediated transport	1	121.5×	0.013	KCNJ11
Cardiac conduction	1	108.8×	0.013	KCNJ11
Muscle contraction	1	77.2×	0.017	KCNJ11
Neuronal System	1	44.3×	0.027	KCNJ11
Transport of small molecules	1	25.1×	0.045	KCNJ11
Disease	1	13.1×	0.081	KCNJ11
Metabolism	1	11.6×	0.086	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to resveratrol	1	3370.4×	0.003	KCNJ11
CAMKK-AMPK signaling cascade	1	2808.7×	0.003	KCNJ11
ventricular cardiac muscle tissue development	1	2106.5×	0.003	KCNJ11
nervous system process	1	1203.7×	0.004	KCNJ11
response to ATP	1	991.3×	0.004	KCNJ11
obsolete inorganic cation transmembrane transport	1	936.2×	0.004	KCNJ11
regulation of monoatomic ion transmembrane transport	1	732.7×	0.004	KCNJ11
negative regulation of insulin secretion	1	495.6×	0.004	KCNJ11
cellular response to nutrient levels	1	468.1×	0.004	KCNJ11
determination of adult lifespan	1	432.1×	0.004	KCNJ11
regulation of insulin secretion	1	391.9×	0.004	KCNJ11
potassium ion import across plasma membrane	1	366.4×	0.004	KCNJ11
action potential	1	358.6×	0.004	KCNJ11
glucose metabolic process	1	255.3×	0.005	KCNJ11
response to ischemia	1	251.5×	0.005	KCNJ11
regulation of membrane potential	1	230.8×	0.005	KCNJ11
potassium ion transmembrane transport	1	135.9×	0.009	KCNJ11
response to hypoxia	1	95.8×	0.012	KCNJ11
response to xenobiotic stimulus	1	69.1×	0.015	KCNJ11
apoptotic process	1	28.7×	0.035	KCNJ11

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
KCNJ11	PINACIDIL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNJ11	102	Functional:59, Binding:43

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNJ11	102

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

7 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)
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNJ11
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns