DEND syndrome

Summary

DEND syndrome (MONDO:0019207) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0003074	Hyperglycemia	Obligate (100%)
HP:0040217	Elevated hemoglobin A1c	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011342	Mild global developmental delay	Frequent (30-79%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002714	Downturned corners of mouth	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0005487	Prominent metopic ridge	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0009894	Thickened ears	Occasional (5-29%)
HP:0040025	Clinodactyly of the 4th finger	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	DEND syndrome
Mondo ID	MONDO:0019207
Orphanet	79134
NCIT	C131845
SNOMED CT	721088003
UMLS	C4303593
MedGen	929262
GARD	0016701
Is cancer (heuristic)	no

Also known as: developmental delay-epilepsy-neonatal diabetes syndrome · K ATP associated developmental delay, epilepsy and neonatal diabetes

Data availability: 1 ClinVar variant · 2 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 › diabetes mellitus › monogenic diabetes › neonatal diabetes mellitus › permanent neonatal diabetes mellitus › DEND syndrome

Related subtypes (4): diabetes mellitus, permanent neonatal 2, diabetes mellitus, permanent neonatal 3, diabetes mellitus, permanent neonatal 4, permanent neonatal diabetes mellitus 1

Subtypes (3): intermediate DEND syndrome, developmental delay, epilepsy, and neonatal diabetes 1, developmental delay, epilepsy, and neonatal diabetes 2

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 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
522957	NM_000525.4(KCNJ11):c.368dup (p.Ser124fs)	KCNJ11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 57 · Orphanet: 15 · 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	Supportive	Autosomal dominant	DEND syndrome	32
KCNJ11	Supportive	Autosomal dominant	DEND syndrome	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
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	gencc,clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc

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.
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: 2 · 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	55.8×	0.026
Transporter	1	38.9×	0.026

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
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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
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
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCC8	2,826
KCNJ11	1,715

Intra-cohort edges

A	B	Sources
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNJ11	Q14654	9
ABCC8	Q09428	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (2 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 2 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	5710.0×	3e-07	KCNJ11, ABCC8
ATP sensitive Potassium channels	2	2855.0×	8e-07	KCNJ11, ABCC8
Inwardly rectifying K+ channels	2	713.8×	1e-05	KCNJ11, ABCC8
ABC transporter disorders	2	439.2×	2e-05	KCNJ11, ABCC8
Regulation of insulin secretion	2	219.6×	7e-05	KCNJ11, ABCC8
Integration of energy metabolism	2	175.7×	9e-05	KCNJ11, ABCC8
Disorders of transmembrane transporters	2	139.3×	1e-04	KCNJ11, ABCC8
Potassium Channels	2	134.3×	1e-04	KCNJ11, ABCC8
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	2855.0×	7e-04	KCNJ11
Neuronal System	2	44.3×	9e-04	KCNJ11, ABCC8
Disease	2	13.1×	0.009	KCNJ11, ABCC8
Metabolism	2	11.6×	0.010	KCNJ11, ABCC8
Ion homeostasis	1	102.0×	0.013	KCNJ11
ABC-family protein mediated transport	1	60.7×	0.020	KCNJ11
Cardiac conduction	1	54.4×	0.021	KCNJ11
Muscle contraction	1	38.6×	0.027	KCNJ11
Transport of small molecules	1	12.6×	0.078	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete inorganic cation transmembrane transport	2	936.2×	5e-05	KCNJ11, ABCC8
negative regulation of insulin secretion	2	495.6×	5e-05	KCNJ11, ABCC8
cellular response to nutrient levels	2	468.1×	5e-05	KCNJ11, ABCC8
regulation of insulin secretion	2	391.9×	5e-05	KCNJ11, ABCC8
potassium ion import across plasma membrane	2	366.4×	5e-05	KCNJ11, ABCC8
action potential	2	358.6×	5e-05	KCNJ11, ABCC8
potassium ion transmembrane transport	2	135.9×	3e-04	KCNJ11, ABCC8
negative regulation of neuroblast migration	1	8426.0×	6e-04	ABCC8
positive regulation of uterine smooth muscle relaxation	1	8426.0×	6e-04	ABCC8
response to xenobiotic stimulus	2	69.1×	9e-04	KCNJ11, ABCC8
glutamate secretion, neurotransmission	1	2808.7×	0.001	ABCC8
negative regulation of blood-brain barrier permeability	1	2808.7×	0.001	ABCC8
response to resveratrol	1	1685.2×	0.002	KCNJ11
positive regulation of tight junction disassembly	1	1685.2×	0.002	ABCC8
response to pH	1	1404.3×	0.002	ABCC8
CAMKK-AMPK signaling cascade	1	1404.3×	0.002	KCNJ11
ventricular cardiac muscle tissue development	1	1053.2×	0.002	KCNJ11
positive regulation of potassium ion transport	1	1053.2×	0.002	ABCC8
negative regulation of glial cell proliferation	1	842.6×	0.003	ABCC8
negative regulation of low-density lipoprotein particle clearance	1	766.0×	0.003	ABCC8
nervous system process	1	601.9×	0.003	KCNJ11
response to ATP	1	495.6×	0.004	KCNJ11
regulation of monoatomic ion transmembrane transport	1	366.4×	0.005	KCNJ11
response to zinc ion	1	312.1×	0.006	ABCC8
intracellular glucose homeostasis	1	290.6×	0.006	ABCC8
neuromuscular process	1	263.3×	0.006	ABCC8
determination of adult lifespan	1	216.1×	0.007	KCNJ11
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.008	ABCC8
visual learning	1	153.2×	0.009	ABCC8
glucose metabolic process	1	127.7×	0.011	KCNJ11

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 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
ABCC8	REPAGLINIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4
ABCC8	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	ABCC8, KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	ABCC8, KCNJ11
REPAGLINIDE	4	ABCC8
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, 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
ABCC8	84	Functional:52, Binding:32

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: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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	ABCC8, KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	ABCC8, KCNJ11
REPAGLINIDE	4	ABCC8
CROMAKALIM	2	ABCC8, KCNJ11
CLAMIKALANT	2	ABCC8, KCNJ11
TIFENAZOXIDE	2	ABCC8, KCNJ11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNJ11, 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: 0.