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ETFDH

electron transfer flavoprotein dehydrogenase

The ETFDH gene provides instructions for an enzyme crucial in breaking down fats and proteins to generate energy within the body's cells. The ETFDH gene encodes the electron transfer flavoprotein dehydrogenase enzyme, which plays a vital role in mitochondrial energy production.

Chromosome 4q32.1 Autosomal recessive HGNC:3483 Tier C
ETFDH 4q32.1 p arm q arm 4

ETFDH is located on the long (q) arm of chromosome 4, at band 4q32.1. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 4 in the library →

Available at Jeen Health

Clinical tests that include this

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

Overview

The ETFDH gene, or electron transfer flavoprotein dehydrogenase, is central to metabolic processes in human cells. It provides the genetic blueprint for an enzyme located within the mitochondria, often referred to as the 'powerhouses' of the cell. This enzyme is indispensable for converting fats and proteins into usable energy.

What the gene does

The ETFDH gene is responsible for producing the electron transfer flavoprotein dehydrogenase enzyme. This enzyme is specifically active within the mitochondria, the organelles where cellular respiration and energy production occur. Its primary role involves the crucial breakdown of fatty acids and certain amino acids, which are derived from dietary fats and proteins, into components that the cell can then use to generate ATP, the body's main energy currency. Without a properly functioning ETFDH enzyme, these metabolic pathways can be disrupted, leading to an accumulation of harmful by-products.

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Chromosome location

The ETFDH gene is situated on the long arm of chromosome 4, specifically at position 4q32.1. This genomic location specifies where the gene resides within the human genome.

Protein structure

The electron transfer flavoprotein dehydrogenase protein, encoded by the ETFDH gene, is composed of 617 amino acids. It features a key structural element, the 4Fe-4S ferredoxin-type domain, located between amino acids 577 and 606. This domain is critical for the protein's ability to facilitate electron transfer reactions.

Domain map · 617 amino acids
4Fe-4S ferredoxin-type (577-606)4Fe-4S ferredoxin577-6061~309617
Domain - independent functional unit
🧬 Explore 3D structure on AlphaFold
UniProt:Q16134Length:617 aaStructure:AlphaFold

Key variants

Variants within the ETFDH gene can impact the structure and function of the electron transfer flavoprotein dehydrogenase enzyme. Some genetic changes may prevent the enzyme from being produced at all, while others can lead to the production of a dysfunctional enzyme. These alterations can disrupt the body's ability to process fats and proteins efficiently.

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for ETFDH.
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.1067G>A
single nucleotide variant
 p.Gly356Glu Pathogenic/Likely pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.1083C>G
single nucleotide variant
 p.Tyr361Ter Pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.1349_1350del
Deletion
 p.Ser450fs Pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.1368_1371del
Deletion
 p.Ser457fs Pathogenic/Likely pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.1675C>T
single nucleotide variant
 p.Arg559Ter Pathogenic ★★☆☆ Glutaric acidemia type 2C
c.1691-3C>G
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Glutaric acidemia type 2C
c.1842_1845dup
Duplication
 p.Gly616fs Pathogenic/Likely pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.40del
Deletion
 p.Gln14fs Pathogenic/Likely pathogenic ★★☆☆ Glutaric acidemia type 2C
c.430G>T
single nucleotide variant
 p.Glu144Ter Pathogenic/Likely pathogenic ★★☆☆ Multiple acyl-CoA dehydrogenase deficiency
c.736G>A
single nucleotide variant
 p.Glu246Lys Pathogenic/Likely pathogenic ★★☆☆ Glutaric acidemia type 2C

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 ETFDH gene are linked to inherited metabolic conditions, most notably Glutaric aciduria type II (which can be riboflavin-responsive) and Multiple acyl-CoA dehydrogenase deficiency (MADD). These conditions are autosomal recessive, meaning an individual must inherit a variant from each parent to be affected. Both disorders involve impaired breakdown of fats and proteins, leading to a build-up of metabolic intermediates.

Inheritance pattern

Conditions caused by pathogenic ETFDH 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 ETFDH carrier status across ancestry groups?

UK clinical status

In the UK, the ETFDH gene is recognised on several NHS Genomic Medicine Service national test panels, indicating its clinical significance. It is listed as 'green' for conditions such as Acute rhabdomyolysis, DDG2P, Foetal anomalies (R21), Hereditary neuropathy or pain disorder (R78), Hyperammonaemia, Inherited white matter disorders, Intellectual disability, Likely inborn error of metabolism (R98), Mitochondrial disorders, Possible mitochondrial disorder, nuclear genes (R63), Rhabdomyolysis and metabolic muscle disorders, and Undiagnosed metabolic disorders, and White matter disorders and cerebral calcification - childhood onset.

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 → Possible mitochondrial disorder, nuclear genes · R63 NHS GMS → DDG2P NHS GMS → Intellectual disability NHS GMS → Mitochondrial 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 primary function of the ETFDH gene?

The ETFDH gene provides instructions for an enzyme called electron transfer flavoprotein dehydrogenase. This enzyme is crucial for breaking down fats and proteins in the mitochondria, thereby helping cells produce energy.

What conditions are associated with variants in the ETFDH gene?

Variants in the ETFDH gene are primarily associated with inherited metabolic disorders such as Glutaric aciduria type II and Multiple acyl-CoA dehydrogenase deficiency (MADD). These conditions affect the body's ability to process fats and proteins.

How is Glutaric aciduria type II inherited?

Glutaric aciduria type II is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic ETFDH gene variant, one from each parent, to develop the condition.

References

  1. Olsen RK, Olpin SE, Andresen BS. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain : a journal of neurology. 2007. PMID: 17584774
  2. Olsen RK, Andresen BS, Christensen E. DNA-based prenatal diagnosis for severe and variant forms of multiple acyl-CoA dehydrogenation deficiency. Prenatal diagnosis. 2005. PMID: 15662686
  3. Olsen RK, Andresen BS, Christensen E. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Human mutation. 2003. PMID: 12815589
  4. Goodman SI, Binard RJ, Woontner MR. Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. Molecular genetics and metabolism. 2002. PMID: 12359134
  5. Spector EB, Seltzer WK, Goodman SI. Assignment of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) to human chromosome 4q33 by fluorescence in situ hybridization and somatic cell hybridization. Molecular genetics and metabolism. 1999. PMID: 10444348
  6. White RA, Dowler LL, Angeloni SV. Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human. Genomics. 1996. PMID: 8617498
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 .