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HADHB

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta

The HADHB gene provides instructions for creating a vital component of the mitochondrial trifunctional protein, which is essential for processing long-chain fatty acids into energy. The HADHB gene is crucial for energy production within cells, specifically through its involvement in breaking down fats.

Chromosome 2p23.3 Autosomal recessive HGNC:4803 Tier C
HADHB 2p23.3 p arm q arm 2

HADHB is located on the short (p) arm of chromosome 2, at band 2p23.3. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 2 in the library →

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Clinical tests that include this

Carrier Screening panel
HADHB is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions
Newborn Genetic Screening panel
HADHB is 1 of 258 genes on this panel
Genomic newborn screening for actionable paediatric conditions

Overview

The HADHB gene, also known as hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta, plays a central role in mitochondrial function. It provides the genetic blueprint for one of the subunits of the mitochondrial trifunctional protein, an enzyme complex vital for metabolising long-chain fatty acids.

Disruptions to HADHB function can lead to impaired energy production, particularly affecting tissues that rely heavily on fatty acids for fuel, such as the heart and muscles.

What the gene does

The HADHB gene encodes the beta subunit of the mitochondrial trifunctional protein (MTP), a large enzyme complex located within the mitochondria, the cell's energy-generating organelles. This complex is composed of four alpha subunits (encoded by the HADHA gene) and four beta subunits (encoded by the HADHB gene). Together, these subunits facilitate fatty acid oxidation, a multi-step process that breaks down fats into usable energy.

Specifically, the HADHB-encoded beta subunits contain the long-chain 3-keto-acyl-CoA thiolase enzyme activity. This enzyme is critical for processing long-chain fatty acids, which are found in various foods and stored in the body's fat tissues. These fatty acids serve as a major energy source, especially for the heart and muscles, and become particularly important for the liver and other tissues during periods of fasting.

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Chromosome location

The HADHB gene is located on chromosome 2, specifically at position 2p23.3. This chromosomal location indicates its precise address within the human genome. The gene spans a region that contains the genetic instructions for producing the HADHB protein.

Protein structure

The HADHB gene encodes a protein consisting of 474 amino acids, which forms the beta subunit of the mitochondrial trifunctional protein. This protein is a key component of the mitochondrial trifunctional protein complex.

Key variants

Variants within the HADHB gene can alter the protein's structure or function, impacting its role in the mitochondrial trifunctional protein complex. These genetic changes may reduce the efficiency of fatty acid oxidation, potentially leading to a build-up of un-metabolised fatty acids and an insufficient supply of cellular energy. Numerous pathogenic variants in the HADHB gene have been identified as causes of mitochondrial trifunctional protein deficiency. Many of these variants involve changes to single amino acids, which are the fundamental building blocks of proteins.

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for HADHB.
View all on ClinVar →

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1112del
Deletion
 p.Asn371fs Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.1389+5G>A
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency 1
c.1390-515_1390-499del
Deletion
 - Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency 2
c.209+1G>C
single nucleotide variant
 - Pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.209C>G
single nucleotide variant
 p.Ser70Ter Pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency
c.340A>G
single nucleotide variant
 p.Asn114Asp Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency 1
c.607C>T
single nucleotide variant
 p.Arg203Ter Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency 1
c.631-1G>A
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency 2
c.811+82A>G
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ HADHB-related disorders
c.962del
Deletion
 p.Met321fs Pathogenic/Likely pathogenic ★★☆☆ Mitochondrial trifunctional protein deficiency

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Pathogenic variants in the HADHB gene are primarily associated with an inherited condition known as Mitochondrial trifunctional protein deficiency. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected. The deficiency can result in a range of symptoms due to impaired fatty acid metabolism. In some cases, specific mutations in HADHB may lead to a reduction in only the long-chain 3-keto-acyl-CoA thiolase enzyme activity of the mitochondrial trifunctional protein.

Inheritance pattern

Conditions caused by pathogenic HADHB variants typically follow autosomal recessive inheritance.

♀ Carrier parent 1 altered copy ♂ Carrier parent 1 altered copy Affected Carrier Carrier Unaffected Affected Carrier Unaffected Circles = females · Squares = males

When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.

Carrier frequency by population How common is heterozygous HADHB carrier status across ancestry groups?

UK clinical status

In the UK, the HADHB gene is included on several NHS Genomic Medicine Service national panels. These include panels for Acute rhabdomyolysis, Foetal anomalies, Hereditary neuropathy, Hereditary neuropathy or pain disorder, Hyperammonaemia, Likely inborn error of metabolism, Mitochondrial disorders, Paediatric or syndromic cardiomyopathy, Possible mitochondrial disorder (nuclear genes), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Acute rhabdomyolysis · R419 NHS GMS → Fetal anomalies · R21 NHS GMS → Hereditary neuropathy or pain disorder · R78 NHS GMS → Likely inborn error of metabolism · R98 NHS GMS → Paediatric or syndromic cardiomyopathy · R135 NHS GMS → Possible mitochondrial disorder, nuclear genes · R63 NHS GMS → Mitochondrial disorders NHS GMS → Rhabdomyolysis and metabolic muscle disorders NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the HADHB gene?

The HADHB gene provides instructions for making part of the mitochondrial trifunctional protein. This protein complex is crucial for breaking down long-chain fatty acids into energy within the cell's mitochondria.

What condition is associated with HADHB gene variants?

Variants in the HADHB gene are primarily associated with Mitochondrial trifunctional protein deficiency. This condition affects how the body processes certain fats, leading to metabolic issues.

How is Mitochondrial trifunctional protein deficiency inherited?

Mitochondrial trifunctional protein deficiency is inherited in an autosomal recessive manner. This means an individual must inherit a pathogenic variant from each parent to develop the condition.

References

  1. Spiekerkoetter U, Lindner M, Santer R. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. Journal of inherited metabolic disease. 2009. PMID: 19399638
  2. Choi JH, Yoon HR, Kim GH. Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. International journal of molecular medicine. 2007. PMID: 17143551
  3. Das AM, Illsinger S, Lücke T. Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Clinical chemistry. 2006. PMID: 16423905
  4. Angdisen J, Moore VD, Cline JM. Mitochondrial trifunctional protein defects: molecular basis and novel therapeutic approaches. Current drug targets. Immune, endocrine and metabolic disorders. 2005. PMID: 15777202
  5. Shekhawat PS, Matern D, Strauss AW. Fetal fatty acid oxidation disorders, their effect on maternal health and neonatal outcome: impact of expanded newborn screening on their diagnosis and management. Pediatric research. 2005. PMID: 15817498
  6. Oey NA, den Boer ME, Wijburg FA. Long-chain fatty acid oxidation during early human development. Pediatric research. 2005. PMID: 15845636
  7. Sander J, Sander S, Steuerwald U. Neonatal screening for defects of the mitochondrial trifunctional protein. Molecular genetics and metabolism. 2005. PMID: 15896654
  8. Spiekerkoetter U, Khuchua Z, Yue Z. General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatric research. 2004. PMID: 14630990
  9. Spierkerkoetter U, Khuchua Z, Yue Z. The early-onset phenotype of mitochondrial trifunctional protein deficiency: a lethal disorder with multiple tissue involvement. Journal of inherited metabolic disease. 2004. PMID: 15243991
  10. Spiekerkoetter U, Sun B, Khuchua Z. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Human mutation. 2003. PMID: 12754706
  11. Eaton S, Bursby T, Middleton B. The mitochondrial trifunctional protein: centre of a beta-oxidation metabolon? Biochemical Society transactions. 2000. PMID: 10816122
  12. Orii KE, Aoyama T, Wakui K. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Human molecular genetics. 1997. PMID: 9259266
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 4 October 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .