Hyperinsulinemic hypoglycemia, familial, 4

Summary

Hyperinsulinemic hypoglycemia, familial, 4 (MONDO:0012382) is a disease caused by HADH (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: HADH (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 69
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0100950	Decreased 3-hydroxyacyl-CoA dehydrogenase level	Obligate (100%)
HP:0000825	Hyperinsulinemic hypoglycemia	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001289	Confusion	Very frequent (80-99%)
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0001397	Hepatic steatosis	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0001998	Neonatal hypoglycemia	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002173	Hypoglycemic seizures	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003215	Dicarboxylic aciduria	Very frequent (80-99%)
HP:0003508	Proportionate short stature	Very frequent (80-99%)
HP:0006929	Hypoglycemic encephalopathy	Very frequent (80-99%)
HP:0008283	Fasting hyperinsulinemia	Very frequent (80-99%)
HP:0012071	Abnormality of acetylcarnitine metabolism	Very frequent (80-99%)
HP:0030781	Increased circulating free fatty acid level	Very frequent (80-99%)
HP:0030796	Increased C-peptide level	Very frequent (80-99%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001987	Hyperammonemia	Occasional (5-29%)
HP:0003128	Lactic acidosis	Occasional (5-29%)
HP:0003234	Decreased circulating carnitine concentration	Occasional (5-29%)
HP:0008151	Prolonged prothrombin time	Occasional (5-29%)
HP:0008180	Mildly elevated creatine kinase	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Very rare (<1-4%)
HP:0001644	Dilated cardiomyopathy	Very rare (<1-4%)
HP:0001657	Prolonged QT interval	Very rare (<1-4%)
HP:0002605	Hepatic necrosis	Very rare (<1-4%)
HP:0002913	Myoglobinuria	Very rare (<1-4%)
HP:0006554	Acute hepatic failure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperinsulinemic hypoglycemia, familial, 4
Mondo ID	MONDO:0012382
MeSH	C566493
OMIM	609975
Orphanet	71212
DOID	DOID:0070215
SNOMED CT	721236002
UMLS	C1864948
MedGen	400646
GARD	0009870
Is cancer (heuristic)	no

Also known as: 3-alpha hydroxyacyl-CoA dehydrogenase deficiency · 3-Alpha-hydroxyacyl-Coenzyme A dehydrogenase deficiency · 3-hydroxyacyl-Coenzyme A dehydrogenase deficiency · 3-hydroxylacyl-CoA dehydrogenase deficiency · had deficiency · HADH deficiency · HADH hyperinsulinemic hypoglycemia (disease) · HADHSC deficiency · HHF4 · hyperinsulinemic hypoglycemia (disease) caused by mutation in HADH · hyperinsulinemic hypoglycemia due to HADH deficiency · hyperinsulinemic hypoglycemia due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency · hyperinsulinemic hypoglycemia, familial, 4 · hyperinsulinemic hypoglycemia, familial, type 4 · hyperinsulinism due to glutamodehydrogenase deficiency · hyperinsulinism due to SCHAD deficiency · hyperinsulinism due to short chain 3-hydroxyacyl-coenzyme a dehydrogenase deficiency · hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency · L-3-Alpha-hydroxyacyl-CoA dehydrogenase, short chain, deficiency · M-SCHAD deficiency (+3 more)

Data availability: 69 ClinVar variants · 2 GenCC gene-disease records.

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 › hyperinsulinemic hypoglycemia, familial, 4

Related subtypes (7): hyperinsulinism-hyperammonemia syndrome, 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, 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

69 retrieved; paginated sample, class counts are floors:

36 conflicting classifications of pathogenicity, 8 benign/likely benign, 7 uncertain significance, 5 uncertain significance/uncertain risk allele, 5 pathogenic, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
39482	NM_005327.7(HADH):c.706C>T (p.Arg236Ter)	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39483	NC_000004.12:g.107986495_107992009del	HADH	Pathogenic	no assertion criteria provided
39484	NM_005327.7(HADH):c.636+471G>T	HADH	Pathogenic	no assertion criteria provided
4056485	Single allele	HADH	Pathogenic	criteria provided, single submitter
8020	NM_005327.7(HADH):c.773C>T (p.Pro258Leu)	HADH	Pathogenic	no assertion criteria provided
802082	NM_005327.7(HADH):c.261+1G>A	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802083	NM_005327.7(HADH):c.587del (p.Ser196fs)	HADH	Pathogenic/Likely pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
8021	NM_005327.7(HADH):c.547-3_549del	HADH	Pathogenic	no assertion criteria provided
1805045	NM_005327.7(HADH):c.434C>A (p.Ala145Asp)	HADH	Likely pathogenic	criteria provided, single submitter
2675956	NM_005327.7(HADH):c.262-2A>G	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589733	NM_005327.7(HADH):c.132+1G>A	HADH	Likely pathogenic	criteria provided, single submitter
659541	NM_005327.7(HADH):c.100G>C (p.Gly34Arg)	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
347124	NM_005327.7(HADH):c.-115del	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
347135	NM_005327.7(HADH):c.889G>A (p.Val297Ile)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
8019	NM_005327.7(HADH):c.171C>A (p.Asp57Glu)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
902197	NM_005327.7(HADH):c.809C>T (p.Thr270Met)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
902198	NM_005327.7(HADH):c.823G>A (p.Asp275Asn)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1312503	NM_005327.7(HADH):c.907G>A (p.Gly303Ser)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211125	NM_005327.7(HADH):c.132+7G>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211127	NM_005327.7(HADH):c.456G>T (p.Gln152His)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212734	NM_005327.7(HADH):c.676T>C (p.Tyr226His)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2499170	NM_005327.7(HADH):c.710-822C>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347130	NM_005327.7(HADH):c.-36C>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347131	NM_005327.7(HADH):c.21G>A (p.Gln7=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347132	NM_005327.7(HADH):c.72G>A (p.Lys24=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347133	NM_005327.7(HADH):c.240G>A (p.Lys80=)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347136	NM_005327.7(HADH):c.*59G>A	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347138	NM_005327.7(HADH):c.*305T>A	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347139	NM_005327.7(HADH):c.*600C>T	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
393392	NM_005327.7(HADH):c.662G>A (p.Arg221His)	HADH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
HADH	Strong	Autosomal recessive	hyperinsulinemic hypoglycemia, familial, 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADH	Orphanet:71212	Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency

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
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS

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
heart right ventricle	1
islet of Langerhans	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADH	2,386

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADH	Q16836	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	2284.0×	6e-04	HADH
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	2284.0×	6e-04	HADH
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	2284.0×	6e-04	HADH
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	2284.0×	6e-04	HADH
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	1903.3×	6e-04	HADH
Mitochondrial protein degradation	1	114.2×	0.009	HADH

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
negative regulation of insulin secretion	1	495.6×	0.007	HADH
regulation of insulin secretion	1	391.9×	0.007	HADH
fatty acid beta-oxidation	1	374.5×	0.007	HADH
response to activity	1	324.1×	0.007	HADH
response to insulin	1	230.8×	0.008	HADH
positive regulation of cold-induced thermogenesis	1	163.6×	0.009	HADH
response to xenobiotic stimulus	1	69.1×	0.019	HADH
spermatogenesis	1	35.2×	0.032	HADH
cell differentiation	1	29.1×	0.034	HADH

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
HADH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase

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	HADH
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)
HADH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.