hyperinsulinism due to HNF4A deficiency

Summary

hyperinsulinism due to HNF4A deficiency (MONDO:0016988) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 33

Clinical features

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000713	Agitation	Very frequent (80-99%)
HP:0000825	Hyperinsulinemic hypoglycemia	Very frequent (80-99%)
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001259	Coma	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0001520	Large for gestational age	Very frequent (80-99%)
HP:0001649	Tachycardia	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0001998	Neonatal hypoglycemia	Very frequent (80-99%)
HP:0002329	Drowsiness	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003162	Fasting hypoglycemia	Very frequent (80-99%)
HP:0004324	Increased body weight	Very frequent (80-99%)
HP:0004359	Abnormal circulating fatty-acid concentration	Very frequent (80-99%)
HP:0004510	Pancreatic islet-cell hyperplasia	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001994	Renal Fanconi syndrome	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0003076	Glycosuria	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Frequent (30-79%)
HP:0004912	Hypophosphatemic rickets	Frequent (30-79%)
HP:0005979	Metabolic ketoacidosis	Frequent (30-79%)
HP:0006568	Increased hepatic glycogen content	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinism due to HNF4A deficiency
Mondo ID	MONDO:0016988
Orphanet	263455
SNOMED CT	717048002
UMLS	C4274078
MedGen	894506
GARD	0020903
Is cancer (heuristic)	no

Also known as: hyperinsulinemic hypoglycemia due to HNF4A deficiency

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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 › diazoxide-sensitive diffuse hyperinsulinism › hyperinsulinism due to HNF4A deficiency

Related subtypes (7): hyperinsulinism-hyperammonemia syndrome, hyperinsulinemic hypoglycemia, familial, 4, exercise-induced hyperinsulinism, hyperinsulinism due to UCP2 deficiency, autosomal dominant hyperinsulinism due to SUR1 deficiency, autosomal dominant hyperinsulinism due to Kir6.2 deficiency, hyperinsulinism due to HNF1A 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
435436	NM_175914.5(HNF4A):c.200G>A (p.Arg67Gln)	HNF4A	Pathogenic	reviewed by expert panel
435439	NM_175914.5(HNF4A):c.944TGC[6] (p.Leu319dup)	HNF4A	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
HNF4A	Supportive	Autosomal dominant	hyperinsulinism due to HNF4A deficiency	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY

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
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

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
Nuclear receptor	1	385.9×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

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
duodenum	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HNF4A	P41235	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Nephron development	1	878.5×	0.003	HNF4A
Regulation of gene expression in beta cells	1	519.1×	0.003	HNF4A
Nuclear Receptor transcription pathway	1	200.3×	0.005	HNF4A

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
regulation of growth hormone receptor signaling pathway	1	16852.0×	8e-04	HNF4A
obsolete regulation of ornithine metabolic process	1	16852.0×	8e-04	HNF4A
regulation of gastrulation	1	2808.7×	0.003	HNF4A
phospholipid homeostasis	1	991.3×	0.006	HNF4A
sex differentiation	1	842.6×	0.006	HNF4A
signal transduction involved in regulation of gene expression	1	702.2×	0.006	HNF4A
triglyceride homeostasis	1	481.5×	0.007	HNF4A
regulation of lipid metabolic process	1	432.1×	0.007	HNF4A
regulation of insulin secretion	1	391.9×	0.007	HNF4A
lipid homeostasis	1	337.0×	0.008	HNF4A
regulation of circadian rhythm	1	259.3×	0.008	HNF4A
response to glucose	1	255.3×	0.008	HNF4A
rhythmic process	1	251.5×	0.008	HNF4A
blood coagulation	1	173.7×	0.011	HNF4A
cholesterol homeostasis	1	156.0×	0.011	HNF4A
xenobiotic metabolic process	1	149.1×	0.011	HNF4A
negative regulation of cell growth	1	144.0×	0.011	HNF4A
glucose homeostasis	1	130.6×	0.011	HNF4A
lipid metabolic process	1	91.6×	0.015	HNF4A
transcription by RNA polymerase II	1	70.5×	0.018	HNF4A
negative regulation of cell population proliferation	1	42.1×	0.029	HNF4A
negative regulation of DNA-templated transcription	1	31.6×	0.037	HNF4A
cell differentiation	1	29.1×	0.039	HNF4A
positive regulation of DNA-templated transcription	1	27.9×	0.039	HNF4A
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	HNF4A
regulation of transcription by RNA polymerase II	1	11.7×	0.086	HNF4A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HNF4A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HNF4A	106	Binding:97, Functional:9

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HNF4A	106

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HNF4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF4A	106	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.