NDUFA9

protein-coding

NADH:ubiquinone oxidoreductase subunit A9, the group of NADH:ubiquinone oxidoreductase supernumerary subunits|Short chain dehydrogenase/reductase superfamily

Gene summary

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12. [provided by RefSeq, May 2010]

Previous symbols:

NDUFS2L

MANE transcript

NM_005002.5

Inheritance

ClinVar variants

P:14U:132B:56

Top phenotype

Mitochondrial complex I deficiency, nuclear type 26; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr12:4,649,095-4,694,317

External References & Databases

Ensembl (ENSG00000139180)

Transcript & Mutation Effects

hg38 • Region Span ~45.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032630

Submitter: PanelApp Australia

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA9* and *NDUFA9*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 18, 2024. The *NDUFA9* gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit A9, a non-catalytic complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The *NDUFA9* gene was first reported in relation to autosomal recessive *NDUFA9*-related primary mitochondrial disease in 2012 (PMID: 22114105). *NDUFA9* has been associated with one disease entity to date; mitochondrial complex I deficiency, nuclear type 26 [OMIM# 618247]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFA9*-related primary mitochondrial disease. Of note, *NDUFA9* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP v7), with a final classification of Moderate. This current curation for the association with *NDUFA9*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique missense variants identified in three unrelated cases from three publications (PMIDs: 22114105, 28671271, 37970307). Age of onset varies from the neonatal period to childhood, and outcomes are variable. Clinical features in affected individuals include LSS, hypertonia, chorea, dystonia, dysarthria, dysphagia, motor and sensory neuropathy, hearing loss, retinopathy, metabolic acidosis, and complex I deficiency in skeletal muscle and skin fibroblasts. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and by rescue studies in both HEK293T cells (PMID: 23223238) and in patient cells (PMID: 28671271). In summary, there is moderate evidence to support the relationship between *NDUFA9* and autosomal recessive *NDUFA9*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 18, 2024 (SOP Version 10).

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 26LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032630

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA9 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. The NDUFA9 gene encodes the NADH:ubiquinone oxidoreductase (complex I) subunit A9, a non-catalytic complex I accessory protein required for complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The NDUFA9 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 22114105). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique variants identified in two cases from two publications (PMIDs: 22114105, 28671271). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interactions, expression data, and functional alterations observed in patient cells and in non-patient cells (PMIDs: 25613900, 28671271, 23223238, 27509854). In summary, there is moderate evidence to support this gene-disease relationship. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2019 (SOP Version 7).

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 26; Leigh syndromeAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; 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

Comments: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 22114105

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA9 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 180

Inborn genetic diseasesTotal: 62

Mitochondrial complex I deficiency, nuclear type 26Total: 24

not specifiedTotal: 22

NDUFA9-related disorderTotal: 9

Leigh syndromeTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005002.5. 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			1 clinvar	37 clinvar	1 clinvar	39
missense	5 clinvar	2 clinvar	122 clinvar	15 clinvar	3 clinvar	147
nonsense	2 clinvar	3 clinvar	1 clinvar			6
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	7	7	132	52	4	202

Highest pathogenic variant AF is 0.000024078448

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005002.5	RefSeq	NP_004993.1	11	MANE Select
ENST00000266544.10	Ensembl	ENSP00000266544.5	11	MANE Select
ENST00000535050.1	Ensembl	ENSP00000440305.1	4	Standard
ENST00000540688.1	Ensembl	ENSP00000439818.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

mitochondrial electron transport, NADH to ubiquinone
sodium ion transport
circadian rhythm
response to glucose
mitochondrial respiratory chain complex I assembly

Molecular Function

NADH dehydrogenase activity
protein binding
NADH dehydrogenase (ubiquinone) activity
protein-containing complex binding
coenzyme binding

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial respiratory chain complex I
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266544
Coding exons: 11
Length: 40194
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125747
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0866	226	230	0.984	0.0000132	2441
Missense (PolyPhen)		53	64.659	0.81969		753
Synonymous	-0.280	84	80.8	1.04	0.00000448	752
Loss of Function	2.84	8	22.6	0.355	0.00000140	231

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000098	0.000098	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. {ECO:0000269|PubMed:22114105, ECO:0000269|PubMed:27626371}.;
Disease: DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:22114105}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.170

Intolerance Scores

LoFtool: 0.314
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.978

Gene Damage Prediction

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