Curated summary · agent-written · kb/genes/curated/hgnc_4799.md

All 14 claims checked against the KB draft

HADH across dismech

HADH (hydroxyacyl-CoA dehydrogenase) is named by 3 disorder entries, including 3-Hydroxyacyl-CoA Dehydrogenase Deficiency.

Normal function

ai-gene-review gives HADH's core molecular functions as (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity; and enzyme inhibitor activity, in the mitochondrial matrix, acting in fatty acid beta-oxidation; and negative regulation of insulin secretion.

Causative records

3-Hydroxyacyl-CoA Dehydrogenase Deficiency records the gene as causative with variant origin germline, on the nodes Biallelic HADH Loss of Function (the catalytic defect) and Loss of SCHAD-GDH Inhibitory Interaction (loss of the inhibitory regulation of glutamate dehydrogenase that the review records as a second core function). The two hyperinsulinism entries also type HADH as causative and place it on their glutamate dehydrogenase nodes, for example Glutamate Dehydrogenase Dysregulation (Amino-Acid-Driven HI).

Where the layers disagree

ClinGen's HADH assertion is for obsolete hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency, a MONDO term that is now obsolete, so it matches no dismech entry. The KB and the review share 0 GO process terms by exact identifier.

Underlined values are claims re-computed from the knowledge base each time this page is built. The tables below are the source of truth.

Normal function · from ai-gene-review (Q16836, commit 79fe13b38970) · AI-generated, not KB evidence

HADH (Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial; also known as SCHAD, HAD1, M/SCHAD) is a soluble mitochondrial matrix enzyme that catalyzes the third step of the fatty-acid beta-oxidation spiral: the NAD+-dependent oxidation of L-(3S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA (EC 1.1.1.35). It acts as a homodimer and preferentially oxidizes short- and medium-chain 3-hydroxyacyl-CoA substrates (roughly C4-C10), functionally distinct from the long-chain, membrane-associated mitochondrial trifunctional protein alpha subunit (HADHA). Catalysis uses His158 as a general base assisted by Glu170. Beyond its catalytic role, HADH has a well-documented regulatory (moonlighting) function in pancreatic beta-cells: it binds and inhibits the activation of glutamate dehydrogenase 1 (GLUD1), thereby restraining amino-acid-stimulated insulin secretion. Loss of HADH function causes hyperinsulinaemic hypoglycaemia and a fatty-acid-oxidation disorder, establishing the first known link between beta-oxidation and dysregulated insulin secretion. HADH is expressed in liver, kidney, pancreatic islets, heart, skeletal muscle, and adipose tissue, and in rodents contributes to body-weight regulation and adaptive thermogenesis.

Core enzymatic function: HADH catalyzes the third step of the mitochondrial fatty-acid beta-oxidation spiral, the NAD+-dependent oxidation of L-(3S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA, acting as a soluble homodimer in the mitochondrial matrix and preferring short/medium-chain (C4-C10) substrates.

molecular function: (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity · directly involved in: fatty acid beta-oxidation · locations: mitochondrial matrix

Secondary (moonlighting) regulatory function: in pancreatic beta-cells HADH binds and inhibits the activation of glutamate dehydrogenase 1 (GLUD1), thereby restraining amino-acid-stimulated insulin secretion. Loss of HADH de-represses GLUD1 and causes inappropriate insulin oversecretion (hyperinsulinaemic hypoglycaemia), a phenotype reproduced in Hadh knockout mice and partly independent of beta-oxidation flux. The underlying molecular activity is enzyme (GLUD1) inhibitor activity; the physiological output is negative regulation of insulin secretion.

molecular function: enzyme inhibitor activity · directly involved in: negative regulation of insulin secretion · locations: mitochondrial matrix

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
3-Hydroxyacyl-CoA Dehydrogenase Deficiency	causative germline	mechanism: Biallelic HADH Loss of Function; Loss of SCHAD-GDH Inhibitory Interaction
Congenital Isolated Hyperinsulinism	causative germline	mechanism: Glutamate Dehydrogenase Dysregulation (Amino-Acid-Driven HI) subtype: SCHAD-HI scoped to subtype: SCHAD-HI
Hyperinsulinemic Hypoglycemia	causative germline	mechanism: Glutamate Dehydrogenase Amino-Acid Amplifier Activation

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
obsolete hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency MONDO:0009278	AR	Definitive 2018-06-26	no dismech entry