hyperinsulinism due to HNF1A deficiency

Summary

hyperinsulinism due to HNF1A deficiency (MONDO:0017935) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000825	Hyperinsulinemic hypoglycemia	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001998	Neonatal hypoglycemia	Very frequent (80-99%)
HP:0030796	Increased C-peptide level	Very frequent (80-99%)
HP:0031084	Excessive insulin response to glucagon test	Very frequent (80-99%)
HP:0040299	Decreased circulating free fatty acid level	Very frequent (80-99%)
HP:0000713	Agitation	Frequent (30-79%)
HP:0000842	Hyperinsulinemia	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001069	Episodic hyperhidrosis	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0001985	Hypoketotic hypoglycemia	Frequent (30-79%)
HP:0002173	Hypoglycemic seizures	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0003162	Fasting hypoglycemia	Frequent (30-79%)
HP:0004904	Maturity-onset diabetes of the young	Frequent (30-79%)
HP:0012051	Reactive hypoglycemia	Frequent (30-79%)
HP:0012759	Neurodevelopmental abnormality	Frequent (30-79%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001325	Hypoglycemic coma	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0002591	Polyphagia	Occasional (5-29%)
HP:0007185	Loss of consciousness	Occasional (5-29%)
HP:0009800	Maternal diabetes	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012734	Ketotic hypoglycemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinism due to HNF1A deficiency
Mondo ID	MONDO:0017935
Orphanet	324575
SNOMED CT	721234004
UMLS	C4303475
MedGen	929144
GARD	0021444
Is cancer (heuristic)	no

Also known as: hyperinsulinemic hypoglycemia due to HNF1A 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 HNF1A deficiency

Related subtypes (7): hyperinsulinism-hyperammonemia syndrome, hyperinsulinemic hypoglycemia, familial, 4, exercise-induced hyperinsulinism, hyperinsulinism due to HNF4A deficiency, hyperinsulinism due to UCP2 deficiency, autosomal dominant hyperinsulinism due to SUR1 deficiency, autosomal dominant 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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14945	NM_000545.8(HNF1A):c.827C>A (p.Ala276Asp)	HNF1A	Pathogenic	reviewed by expert panel
1691373	NM_175914.5(HNF4A):c.47dup (p.Tyr16Ter)	HNF4A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · 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
HNF1A	Supportive	Autosomal dominant	hyperinsulinism due to HNF1A deficiency	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
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

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gencc,clinvar
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
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: 1 · Unknown: 0 · Druggable fraction: 0.5

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	192.9×	0.010
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
right lobe of liver	2
liver	1
duodenum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
HNF1A	2,491

Intra-cohort edges

A	B	Sources
HNF1A	HNF4A	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HNF4A	P41235	8
HNF1A	P20823	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Regulation of gene expression in beta cells	2	519.1×	1e-05	HNF1A, HNF4A
Nephron development	1	439.2×	0.003	HNF4A
Nuclear Receptor transcription pathway	1	100.2×	0.010	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 2 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	8426.0×	0.001	HNF4A
obsolete regulation of ornithine metabolic process	1	8426.0×	0.001	HNF4A
glucose homeostasis	2	130.6×	0.001	HNF1A, HNF4A
renal D-glucose absorption	1	2808.7×	0.003	HNF1A
regulation of gastrulation	1	1404.3×	0.005	HNF4A
positive regulation of DNA-templated transcription	2	27.9×	0.007	HNF1A, HNF4A
phospholipid homeostasis	1	495.6×	0.008	HNF4A
sex differentiation	1	421.3×	0.008	HNF4A
obsolete D-glucose import	1	421.3×	0.008	HNF1A
signal transduction involved in regulation of gene expression	1	351.1×	0.009	HNF4A
pancreas development	1	337.0×	0.009	HNF1A
triglyceride homeostasis	1	240.7×	0.010	HNF4A
regulation of lipid metabolic process	1	216.1×	0.010	HNF4A
insulin secretion	1	216.1×	0.010	HNF1A
positive regulation of transcription by RNA polymerase II	2	14.9×	0.010	HNF1A, HNF4A
regulation of insulin secretion	1	195.9×	0.010	HNF4A
lipid homeostasis	1	168.5×	0.011	HNF4A
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.012	HNF1A
regulation of circadian rhythm	1	129.6×	0.012	HNF4A
response to glucose	1	127.7×	0.012	HNF4A
rhythmic process	1	125.8×	0.012	HNF4A
regulation of transcription by RNA polymerase II	2	11.7×	0.012	HNF1A, HNF4A
liver development	1	110.9×	0.013	HNF1A
blood coagulation	1	86.9×	0.015	HNF4A
cholesterol homeostasis	1	78.0×	0.016	HNF4A
xenobiotic metabolic process	1	74.6×	0.016	HNF4A
negative regulation of cell growth	1	72.0×	0.016	HNF4A
lipid metabolic process	1	45.8×	0.025	HNF4A
transcription by RNA polymerase II	1	35.3×	0.031	HNF4A
negative regulation of cell population proliferation	1	21.1×	0.050	HNF4A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
HNF1A	0	0
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
HNF1A	1	Binding:1

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: 2; 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	1	HNF1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF4A	106	—
HNF1A	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.