HADHA

protein-coding

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha

Gene summary

This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000182.5

Inheritance

ClinVar variants

P:278U:258B:329

Top phenotype

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency 1

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr2:26,190,635-26,244,672

External References & Databases

Ensembl (ENSG00000084754)

Transcript & Mutation Effects

hg38 • Region Span ~54.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: ClinGen

*HADHA* was first reported in relation to autosomal recessive long chain 3-hydroxyacyl-CoA dehydrogenase deficiency in 1994 (IJlst et al., PMID: 7811722). Seven variants (missense, nonsense, frameshift) that have been reported in 10 probands in 4 publications (PMIDs: 7811722, 10518281, 21103935, 9739053) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency is characterized by early-onset cardiomyopathy, hypoglycemia, neuropathy, and retinopathy. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by a mouse model (PMID:11390422) and functional assays in patient cells showing reduced long-chain 3-hydroxyacyl-CoA dehydrogenase activity (PMID: 8770876). In summary, there is definitive evidence supporting the relationship between *HADHA* and autosomal recessive long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Fatty Acid Oxidation Disorders GCEP on February 12th, 2018 (SOP Version 6).

mitochondrial trifunctional protein deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012172

Submitter: Labcorp Genetics (formerly Invitae)

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: Labcorp Genetics (formerly Invitae)

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: G2P

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: Orphanet

mitochondrial trifunctional protein deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012172

Submitter: Orphanet

mitochondrial trifunctional protein deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958181

Submitter: PanelApp Australia

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: PanelApp Australia

long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012173

Submitter: Natera

Clinical Genomic Database (CGD)

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency 1AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: Early diagnosis to allow interventions such as avoidance of fasting and urgent metabolic care in the setting of acute metabolic decompensation can reduce morbidity and mortality; Medical management (such as with triheptanoin) has been described as beneficial

Comments: Variants are also related to maternal HELLP syndrome and Acute fatty liver of pregnancy

Refs: 7813533; 7811722; 7846063; 8770876; 10518281; 12621125; 17143551; 21549624; 21103935; 21630065; 33744096

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HADHA variants in ClinVar

11 Conditions Cataloged

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiencyTotal: 1009

Mitochondrial trifunctional protein deficiencyTotal: 838

not providedTotal: 170

Inborn genetic diseasesTotal: 93

not specifiedTotal: 91

HADHA-related disorderTotal: 79

Mitochondrial trifunctional protein deficiency 1Total: 60

LCHAD deficiency with maternal acute fatty liver of pregnancyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000182.5. 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			12 clinvar	305 clinvar		317
missense	3 clinvar	25 clinvar	238 clinvar	22 clinvar	2 clinvar	290
nonsense	24 clinvar	29 clinvar	1 clinvar			54
start loss		2 clinvar				2
frameshift	67 clinvar	76 clinvar	1 clinvar			144
splice donor/acceptor (+/-2bp)	10 clinvar	42 clinvar	6 clinvar			58
Total	104	174	258	327	2	865

Highest pathogenic variant AF is 0.0013409166

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000182.5	RefSeq	NP_000173.2	20	MANE Select
ENST00000380649.8	Ensembl	ENSP00000370023.3	20	MANE Select
ENST00000492433.2	Ensembl	ENSP00000438039.2	19	Standard
ENST00000492433.3	Ensembl	ENSP00000438039.2	19	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)
beta-Alanine metabolism - Homo sapiens (human)
Lysine degradation - Homo sapiens (human)
Propanoate metabolism - Homo sapiens (human)

Biological Process

fatty acid beta-oxidation
response to insulin
response to drug

Molecular Function

fatty-acyl-CoA binding
3-hydroxyacyl-CoA dehydrogenase activity
acetyl-CoA C-acetyltransferase activity
enoyl-CoA hydratase activity
protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial fatty acid beta-oxidation multienzyme complex
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380649
Coding exons: 20
Length: 54091
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.821	355	401	0.885	0.0000218	4942
Missense (PolyPhen)		119	163.63	0.72726		2019
Synonymous	-0.580	161	152	1.06	0.00000880	1532
Loss of Function	3.43	16	39.1	0.409	0.00000204	500

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00038	0.00035	rare
South Asian	0.00052	0.00052	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Bifunctional subunit.;
Disease: DISEASE: Mitochondrial trifunctional protein deficiency (MTPD) [MIM:609015]: A disease biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. Variable clinical manifestations include hypoglycemia, cardiomyopathy, delayed psychomotor development, sensorimotor axonopathy, generalized weakness, hepatic dysfunction, respiratory failure. Sudden infant death may occur. Most patients die from heart failure. {ECO:0000269|PubMed:9739053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) [MIM:609016]: The clinical features are very similar to TFP deficiency. Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the TFP complex are normal or only slightly reduced. {ECO:0000269|PubMed:7811722, ECO:0000269|PubMed:9266371}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Maternal acute fatty liver of pregnancy (AFLP) [MIM:609016]: Severe maternal illness occurring during pregnancies with affected fetuses. This disease is associated with LCHAD deficiency and characterized by sudden unexplained infant death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). {ECO:0000269|PubMed:7846063}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.516

Intolerance Scores

LoFtool: 0.347
RVIS EVS: -0.64
RVIS percentile EVS: 16.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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