HADH

protein-coding

hydroxyacyl-CoA dehydrogenase

Gene summary

This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

Previous symbols:

HADHSC

MANE transcript

NM_005327.7

Inheritance

ClinVar variants

P:41U:100B:99

Top phenotype

3-hydroxyacyl-CoA dehydrogenase deficiency; Hyperinsulinemic hypoglycemia, familial, 4

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr4:107,989,714-108,035,241

External References & Databases

Ensembl (ENSG00000138796)

Transcript & Mutation Effects

hg38 • Region Span ~45.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009278

Submitter: Orphanet

hyperinsulinemic hypoglycemia, familial, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012382

Submitter: Labcorp Genetics (formerly Invitae)

hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009278

Submitter: ClinGen

3-hydroxyacyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017715

Submitter: G2P

hyperinsulinemic hypoglycemia, familial, 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012382

Submitter: PanelApp Australia

3-hydroxyacyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017715

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

3-hydroxyacyl-CoA dehydrogenase deficiency; Hyperinsulinemic hypoglycemia, familial, 4AR

Manifestation: Biochemical; Endocrine; Gastrointestinal

Intervention: Cardiovascular; Endocrine; Gastrointestinal

Rationale: Individuals may present with hypoglycemic seizures, which can lead to neurologic sequelae, and measures to treat/prevent hypoglycemia (eg, with diazoxide) can be effective; In the longer-term, medical and/or surgical treatment (eg, with pancreatectomy, glucagon) may help prevent severe sequelae; In 3-hydroxyacyl-CoA dehydrogenase deficiency, surveillance for cardiovascular manifestations (eg, cardiomyopathy) may allow prompt management; Liver transplant has been described

Refs: 4193973; 904979; 1835339; 10347277; 10931422; 11489939; 12400064; 14693719; 15870679; 16725361; 19417036; 19318379; 20301549; 21347589; 23273570

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HADH variants in ClinVar

10 Conditions Cataloged

Deficiency of 3-hydroxyacyl-CoA dehydrogenaseTotal: 259

not providedTotal: 51

Hyperinsulinemic hypoglycemiaTotal: 47

Hyperinsulinemic hypoglycemia, familial, 4Total: 41

Inborn genetic diseasesTotal: 40

HADH-related disorderTotal: 26

not specifiedTotal: 21

Monogenic diabetesTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005327.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	90 clinvar		92
missense	1 clinvar	9 clinvar	97 clinvar	8 clinvar	1 clinvar	116
nonsense	1 clinvar	3 clinvar				4
start loss	1 clinvar					1
frameshift	8 clinvar	6 clinvar	1 clinvar			15
splice donor/acceptor (+/-2bp)	3 clinvar	9 clinvar				12
Total	14	27	100	98	1	240

Highest pathogenic variant AF is 0.00018618669

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 51 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005327.7	RefSeq	NP_005318.6	8	MANE Select
ENST00000309522.8	Ensembl	ENSP00000312288.4	8	MANE Select
NM_001184705.4	RefSeq	NP_001171634.3	9	Standard
NM_001331027.2	RefSeq	NP_001317956.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tryptophan metabolism - Homo sapiens (human)
Butanoate metabolism - Homo sapiens (human)
Lysine degradation - Homo sapiens (human)
Fatty acid degradation - Homo sapiens (human)
Fatty acid elongation - Homo sapiens (human)

Biological Process

fatty acid beta-oxidation
response to activity
response to insulin
response to drug
negative regulation of insulin secretion

Molecular Function

3-hydroxyacyl-CoA dehydrogenase activity
NAD+ binding

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000603302
Coding exons: 9
Length: 45462
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.528	163	183	0.890	0.00000981	2175
Missense (PolyPhen)		40	61.125	0.6544		739
Synonymous	-0.350	79	75.1	1.05	0.00000465	648
Loss of Function	1.57	9	15.7	0.572	8.57e-7	184

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an essential role in the mitochondrial beta- oxidation of short chain fatty acids. Exerts it highest activity toward 3-hydroxybutyryl-CoA.;
Disease: DISEASE: 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency) [MIM:231530]: An autosomal recessive, metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death. {ECO:0000269|Ref.13}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial hyperinsulinemic hypoglycemia 4 (HHF4) [MIM:609975]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion. {ECO:0000269|PubMed:11489939}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.314

Intolerance Scores

LoFtool: 0.312
RVIS EVS: 0.82
RVIS percentile EVS: 87.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.896

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium