Hyperinsulinemic hypoglycemia, familial, 1

Summary

Hyperinsulinemic hypoglycemia, familial, 1 (MONDO:0009734) is a disease caused by ABCC8 (GenCC Definitive), with 7 cohort genes.

At a glance

• Causal gene: ABCC8 (GenCC Definitive)
• Cohort genes: 7
• ClinVar variants: 761

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinemic hypoglycemia, familial, 1
Mondo ID	MONDO:0009734
OMIM	256450
DOID	DOID:0070219
SNOMED CT	360339005
UMLS	C2931832
MedGen	419505
GARD	0024690
Is cancer (heuristic)	no

Also known as: ABCC8 hyperinsulinemic hypoglycemia (disease) · HHF1 · hyperinsulinemic hypoglycemia (disease) caused by mutation in ABCC8 · hyperinsulinemic hypoglycemia due to SUR1 deficiency · hyperinsulinemic hypoglycemia, familial, 1 · hyperinsulinemic hypoglycemia, familial, type 1

Data availability: 761 ClinVar variants · 8 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › hyperinsulinemic hypoglycemia › hyperinsulinemic hypoglycemia, familial, 1

Related subtypes (4): familial hyperinsulinism, insulin autoimmune syndrome, hyperinsulinemic hypoglycemia, familial, 8, hyperinsulinemic hypoglycemia with polycystic kidney disease

Subtypes (2): diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency, autosomal recessive hyperinsulinism due to SUR1 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

600 retrieved; paginated sample, class counts are floors:

228 uncertain significance, 144 conflicting classifications of pathogenicity, 81 likely pathogenic, 50 pathogenic, 50 pathogenic/likely pathogenic, 31 likely benign, 10 benign/likely benign, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065615	NM_000352.6(ABCC8):c.4369G>A (p.Ala1457Thr)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1071311	NM_000352.6(ABCC8):c.1332G>T (p.Gln444His)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073510	NM_000352.6(ABCC8):c.2113C>T (p.Arg705Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1075098	NM_000352.6(ABCC8):c.3000C>A (p.Cys1000Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076249	NM_000352.6(ABCC8):c.1647del (p.Ile550fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179142	NM_000352.6(ABCC8):c.1893del (p.Gln632fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1338472	NM_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1338676	NM_000352.6(ABCC8):c.805del (p.Ala269fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1390642	NM_000352.6(ABCC8):c.45C>G (p.Tyr15Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452922	NM_000352.6(ABCC8):c.3773dup (p.Val1259fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1457730	NM_000352.6(ABCC8):c.3988+2T>C	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459964	NM_000352.6(ABCC8):c.502C>T (p.Arg168Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1506182	NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526015	NM_000352.6(ABCC8):c.61del (p.Val21fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526017	NM_000352.6(ABCC8):c.1330C>T (p.Gln444Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1526019	NM_000352.6(ABCC8):c.2694G>A (p.Trp898Ter)	ABCC8	Pathogenic	criteria provided, single submitter
157696	NM_000352.6(ABCC8):c.3509del (p.Leu1170fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1687449	NM_000352.6(ABCC8):c.693G>A (p.Trp231Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687616	NM_000352.6(ABCC8):c.3575dup (p.Asp1192fs)	ABCC8	Pathogenic	criteria provided, single submitter
1705703	NM_000352.6(ABCC8):c.2800C>T (p.Gln934Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
18449	NM_000352.6(ABCC8):c.2147G>T (p.Gly716Val)	ABCC8	Pathogenic	no assertion criteria provided
1878337	NM_000352.6(ABCC8):c.1630+1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188836	NM_000352.6(ABCC8):c.4628T>C (p.Leu1543Pro)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188864	NM_000352.6(ABCC8):c.2797C>T (p.Arg933Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188894	NM_000352.6(ABCC8):c.3124_3126delinsCAGCCAGGAACTG (p.Thr1042fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188905	NM_000352.6(ABCC8):c.2857C>T (p.Gln953Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188915	NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188931	NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
196880	NM_000352.6(ABCC8):c.4160_4162del (p.Phe1387del)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
210072	NM_000352.6(ABCC8):c.2117-1G>A	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 9 · 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	Definitive	Autosomal dominant	hyperinsulinemic hypoglycemia, familial, 1	32

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
BFSP1	Orphanet:98991	Early-onset nuclear cataract
HADH	Orphanet:71212	Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
BFSP1	HGNC:1040	ENSG00000125864	Q12934	Filensin	clinvar
XRN2	HGNC:12836	ENSG00000088930	Q9H0D6	5’-3’ exoribonuclease 2	clinvar
SCP2D1-AS1	HGNC:16210	ENSG00000149443	Q9BR46	Putative uncharacterized protein SCP2D1-AS1	clinvar
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	clinvar
NKX2-2	HGNC:7835	ENSG00000125820	O95096	Homeobox protein Nkx-2.2	clinvar
NKX2-4	HGNC:7837	ENSG00000125816	Q9H2Z4	Homeobox protein Nkx-2.4	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.
BFSP1	Filensin	Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.
XRN2	5’-3’ exoribonuclease 2	Possesses 5’->3’ exoribonuclease activity.
HADH	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).
NKX2-2	Homeobox protein Nkx-2.2	Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas.
NKX2-4	Homeobox protein Nkx-2.4	Probable transcription factor.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.43

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	11.1×	0.220
Enzyme (other)	2	3.4×	0.220
Transcription factor	2	2.4×	0.272
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
BFSP1	Other/Unknown	no		IF_rod_dom, BFSP1
XRN2	Enzyme (other)	yes	3.1.13.1	Xrn1_N, Xrn2/3/4, 5_3_exoribonuclease
SCP2D1-AS1	Other/Unknown	no
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
NKX2-2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
NKX2-4	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
islet of Langerhans	2
primordial germ cell in gonad	2
right testis	2
cerebellar hemisphere	1
right hemisphere of cerebellum	1
tendon of biceps brachii	1
ganglionic eminence	1
leukocyte	1
monocyte	1
left testis	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
inferior vagus X ganglion	1
medulla oblongata	1
subthalamic nucleus	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
BFSP1	176	broad	yes	tendon of biceps brachii, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
XRN2	248	ubiquitous	marker	monocyte, leukocyte, ganglionic eminence
SCP2D1-AS1	69		yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis
NKX2-2	100	tissue_specific	marker	inferior vagus X ganglion, subthalamic nucleus, medulla oblongata
NKX2-4	12	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, right testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XRN2	3,779
ABCC8	2,826
HADH	2,386
NKX2-2	1,670
NKX2-4	624
BFSP1	547
SCP2D1-AS1	0

Intra-cohort edges

A	B	Sources
NKX2-2	NKX2-4	string_interaction
NKX2-4	XRN2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADH	Q16836	12
ABCC8	Q09428	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
XRN2	Q9H0D6	78.15
BFSP1	Q12934	64.66
NKX2-2	O95096	64.62
NKX2-4	Q9H2Z4	59.61
SCP2D1-AS1	Q9BR46	32.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 7 evidence-associated genes (4 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 4 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	1427.5×	0.006	ABCC8
ATP sensitive Potassium channels	1	713.8×	0.006	ABCC8
Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells	1	571.0×	0.006	NKX2-2
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	571.0×	0.006	HADH
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	571.0×	0.006	HADH
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	571.0×	0.006	HADH
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	571.0×	0.006	HADH
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	475.8×	0.006	HADH
Inwardly rectifying K+ channels	1	178.4×	0.014	ABCC8
Regulation of gene expression in beta cells	1	129.8×	0.018	NKX2-2
ABC transporter disorders	1	109.8×	0.019	ABCC8
Nuclear RNA decay	1	77.2×	0.024	XRN2
Association of TriC/CCT with target proteins during biosynthesis	1	73.2×	0.024	XRN2
Regulation of insulin secretion	1	54.9×	0.030	ABCC8
Integration of energy metabolism	1	43.9×	0.035	ABCC8
Disorders of transmembrane transporters	1	34.8×	0.040	ABCC8
Potassium Channels	1	33.6×	0.040	ABCC8
Mitochondrial protein degradation	1	28.6×	0.044	HADH
mRNA Polyadenylation	1	22.0×	0.054	XRN2
Major pathway of rRNA processing in the nucleolus and cytosol	1	15.4×	0.073	XRN2
Neuronal System	1	11.1×	0.096	ABCC8
Disease	1	3.3×	0.285	ABCC8
Metabolism	1	2.9×	0.302	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 6 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 insulin secretion	2	165.2×	0.003	ABCC8, HADH
regulation of insulin secretion	2	130.6×	0.003	ABCC8, HADH
type B pancreatic cell fate commitment	1	2808.7×	0.004	NKX2-2
ventral spinal cord interneuron fate determination	1	2808.7×	0.004	NKX2-2
negative regulation of neuroblast migration	1	2808.7×	0.004	ABCC8
positive regulation of uterine smooth muscle relaxation	1	2808.7×	0.004	ABCC8
response to insulin	2	77.0×	0.004	ABCC8, HADH
pancreatic A cell fate commitment	1	1404.3×	0.005	NKX2-2
pancreatic PP cell fate commitment	1	1404.3×	0.005	NKX2-2
cell differentiation	3	14.6×	0.005	HADH, NKX2-2, NKX2-4
spinal cord oligodendrocyte cell fate specification	1	936.2×	0.006	NKX2-2
glutamate secretion, neurotransmission	1	936.2×	0.006	ABCC8
negative regulation of blood-brain barrier permeability	1	936.2×	0.006	ABCC8
positive regulation of tight junction disassembly	1	561.7×	0.009	ABCC8
response to pH	1	468.1×	0.010	ABCC8
RNA metabolic process	1	468.1×	0.010	XRN2
neuroendocrine cell differentiation	1	401.2×	0.011	NKX2-2
positive regulation of potassium ion transport	1	351.1×	0.011	ABCC8
lens fiber cell development	1	351.1×	0.011	BFSP1
response to xenobiotic stimulus	2	23.0×	0.011	ABCC8, HADH
positive regulation of epithelial cell differentiation	1	312.1×	0.011	NKX2-2
negative regulation of glial cell proliferation	1	280.9×	0.012	ABCC8
negative regulation of low-density lipoprotein particle clearance	1	255.3×	0.012	ABCC8
type B pancreatic cell development	1	216.1×	0.013	NKX2-2
termination of RNA polymerase II transcription	1	216.1×	0.013	XRN2
optic nerve development	1	200.6×	0.014	NKX2-2
spinal cord motor neuron differentiation	1	156.0×	0.017	NKX2-2
obsolete inorganic cation transmembrane transport	1	156.0×	0.017	ABCC8
nuclear-transcribed mRNA catabolic process	1	127.7×	0.019	XRN2
astrocyte differentiation	1	127.7×	0.019	NKX2-2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 3 of 7 evidence-associated genes (43%) 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
BFSP1	0	0
XRN2	0	0
SCP2D1-AS1	0	0
HADH	0	0
NKX2-2	0	0
NKX2-4	0	0

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): 2.

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

Symbol	Assays	Type breakdown
ABCC8	84	Functional:52, Binding:32
XRN2	1	Binding:1
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
XRN2	3.1.13.1	exoribonuclease II
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	HADH
D	Druggable family + AlphaFold only, no drug	1	XRN2
E	Difficult family or no structure, no drug	4	BFSP1, SCP2D1-AS1, NKX2-2, NKX2-4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BFSP1	0	—
XRN2	1	—
SCP2D1-AS1	0	—
HADH	1	—
NKX2-2	0	—
NKX2-4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.