FDXR

protein-coding

ferredoxin reductase, the group of Mitochondrial respiratory chain complex assembly factors|Mitochondrial iron-sulfur assembly components

Gene summary

This gene encodes a mitochondrial flavoprotein that initiates electron transport for cytochromes P450 receiving electrons from NADPH. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]

Previous symbols:

ADXR

MANE transcript

NM_024417.5

Inheritance

ClinVar variants

P:44U:122B:73

Top phenotype

Auditory neuropathy and optic atrophy; Multiple mitochondrial dysfunctions syndrome 9B

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr17:74,862,497-74,873,031

External References & Databases

Ensembl (ENSG00000161513)

Transcript & Mutation Effects

hg38 • Region Span ~10.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

FDXR-related optic atrophy mitochondrial dysfunction syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1060116

Submitter: ClinGen

*FDXR* was first reported in relation to optic atrophy in 2017, in patients with optic atrophy and auditory neuropathy (PMID: 28965846), and in 2018 in patients with optic atrophy and mitochondriopathy (PMID: 29040572). Whole exome sequencing revealed biallelic variants in *FDXR* in probands and affected siblings and heterozygous variants in unaffected parents and siblings in the families. Subsequently, over 50 disease-associated *FDXR* variants have been reported in more than 50 probands with optic atrophy with or without extraocular phenotypes. A few recurrent variants have been reported in cases with primarily optic atrophy as well as cases with optic atrophy and variable extraocular presentations, which can include cerebral atrophy, hearing loss, myopathy, and developmental delay. The phenotypic variability between affected individuals appears to represent a spectrum of disease rather than separate disease entities. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, this curation has included cases reported as auditory neuropathy and optic atrophy (OMIM # 617717) as well as cases reported as multiple mitochondrial dysfunction syndrome 9B (OMIM # 620887), with the lumped disease entity referred to as *FDXR*-related optic atrophy mitochondrial dysfunction syndrome, with an autosomal recessive mode of inheritance. This curation has included and scored twenty-nine unique *FDXR* variants identified in twenty-one probands and reported in six publications (PMID: 28965846, PMID: 29040572, PMID: 33348459, PMID: 33938912, PMID: 38885337, PMID: 39669623). Among the reported variants (missense, nonsense, splice site mutations, frameshift and small deletions), approximately 90% are missense variants. Notably, approximately 25% of cases from 3 publications (PMID: 29040572, PMID: 33348459, PMID: 39669623) were homozygous or compound heterozygous for the p.Arg386Trp variant, with the vast majority of these affected individuals being of Hispanic origin, suggesting a founder effect. This gene-disease relationship is also supported by experimental evidence that *FDXR* encodes ferredoxin reductase, a mitochondrial flavoprotein that serves as an electron transfer protein in the mitochondrial P450 system and is involved in steroid and cholesterol metabolism (PMID: 2845396). Further experimental support is provided by studies showing altered FDXR function in patient-derived cells and recapitulation of clinical features from affected patients in non-human model organisms with successful rescue (PMID: 28965846, PMID: 29040572, PMID: 38885337). In summary, *FDXR* is Definitively associated with FDXR-related optic atrophy mitochondrial dysfunction syndrome. This has been repeatedly demonstrated in both clinical and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on July 17th, 2025 (SOP Version 11).

auditory neuropathy-optic atrophy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060582

Submitter: G2P

optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0034092

Submitter: PanelApp Australia

auditory neuropathy-optic atrophy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060582

Submitter: Labcorp Genetics (formerly Invitae)

optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0034092

Submitter: Orphanet

auditory neuropathy-optic atrophy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060582

Submitter: Orphanet

Clinical Genomic Database (CGD)

Auditory neuropathy and optic atrophy; Multiple mitochondrial dysfunctions syndrome 9BAR

Manifestation: Audiologic/Otolaryngologic; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28965846; 29040572; 30250212; 33348459; 36317462; 37046037; 37107710; 37481223

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FDXR variants in ClinVar

16 Conditions Cataloged

not providedTotal: 117

not specifiedTotal: 97

Inborn genetic diseasesTotal: 91

FDXR-related disorderTotal: 66

Auditory neuropathy-optic atrophy syndromeTotal: 37

Multiple mitochondrial dysfunctions syndrome 9bTotal: 15

Hearing problemTotal: 2

Retinal dystrophyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024417.5. 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			3 clinvar	43 clinvar	3 clinvar	49
missense	3 clinvar	21 clinvar	114 clinvar	24 clinvar	3 clinvar	165
nonsense	2 clinvar	2 clinvar	3 clinvar			7
start loss		2 clinvar				2
frameshift	2 clinvar	7 clinvar				9
splice donor/acceptor (+/-2bp)		5 clinvar	2 clinvar			7
Total	7	37	122	67	6	239

Highest pathogenic variant AF is 0.000048948717

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 98 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024417.5	RefSeq	NP_077728.3	12	MANE Select
ENST00000293195.10	Ensembl	ENSP00000293195.5	12	MANE Select
NM_001258012.4	RefSeq	NP_001244941.2	12	Standard
NM_001258013.4	RefSeq	NP_001244942.2	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phase I - Functionalization of compounds
Electron transport from NADPH to Ferredoxin
Metabolism of lipids
Endogenous sterols
Cytochrome P450 - arranged by substrate type

Biological Process

generation of precursor metabolites and energy
steroid biosynthetic process
C21-steroid hormone biosynthetic process
ubiquinone biosynthetic process
cholesterol metabolic process

Molecular Function

ferredoxin-NADP+ reductase activity
NADPH-adrenodoxin reductase activity
oxidoreductase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000442102
Coding exons: 12
Length: 10538
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125728
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.906	294	341	0.862	0.0000216	3369
Missense (PolyPhen)		82	101.55	0.80752		907
Synonymous	0.740	133	144	0.922	0.00000925	1174
Loss of Function	2.28	14	26.7	0.523	0.00000142	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00039	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydroxylation in the liver. {ECO:0000250|UniProtKB:P08165}.;
Disease: DISEASE: Auditory neuropathy and optic atrophy (ANOA) [MIM:617717]: An autosomal recessive disease characterized by hearing loss, visual impairment and optic atrophy, with onset in the first or second decades of life. Optic atrophy is caused by degeneration of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. {ECO:0000269|PubMed:28965846}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.383

Intolerance Scores

LoFtool: 0.495
RVIS EVS: 0.54
RVIS percentile EVS: 81.07

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.826

Gene Damage Prediction

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