Paediatric or syndromic cardiomyopathy

Gene: NDUFA4

Red List (low evidence)

Comment on list classification: Although there are at least three unrelated patients reported with biallelic variants in NDUFA4 gene, only one patient (one from the UK 100,000 genomes project) presented with cardiomyopathy. Hence, this gene can only be rated red with the current evidence.

Created: 26 Aug 2025, 9:43 a.m. | Last Modified: 28 Aug 2025, 3:10 p.m.

Panel Version: 7.34

Comment on phenotypes: OMIM phenotype accessed on 26 August 2025.

Created: 26 Aug 2025, 9:41 a.m. | Last Modified: 26 Aug 2025, 9:41 a.m.

Panel Version: 7.25

PMID:23746447 (2013) reported a large consanguineous Pakistani family, in which four affected relatives had a neurological disease due to isolated COX deficiency. The affected individuals were identified with a homozygous NDUFA4 variant, which was found in heterozygous state in three unaffected individuals from the family. The patients did not present with any cardiac phenotypes.

PMID:38674434 (2024) reported a 4-year-old Somali female presenting with psychomotor delay and white matter signal changes, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome. The patient was identified with a homozygous 12.9 Kb deletion covering the entire NDUFA4 gene via trio WGS, and this deletion was present in heterozygous state in both parents. However, the patient did not show any cardiac abnormalities, except that the ventricular walls were measured at the higher end of the normal range.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one female patient with hypertrophic cardiomyopathy was identified with homozygous splice donor variant in NDUFA4 gene (c.131+1G>C).

Created: 26 Aug 2025, 9:40 a.m. | Last Modified: 26 Aug 2025, 9:40 a.m.

Panel Version: 7.23

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Mitochondrial complex IV deficiency, nuclear type 21, OMIM:619065; mitochondrial complex IV deficiency, nuclear type 21, MONDO:0033656

Publications

• 23746447
• 38674434
• 39472908

Green List (high evidence)

Updated information and Green review collated by Carl Fratter May 2019 on behalf of GMS mitochondrial specialist test group: 1 family (4 affecteds) reported with functional studies; also London team have diagnosed a second unrelated family; note that this is a Complex IV subunit.

Created: 10 May 2019, 11:13 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex IV deficiency

Publications

• 23746447
• 29636225

Comment on list classification: This gene was promoted from Amber to Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter.

Created: 10 May 2019, 12:05 p.m.

Comment on list classification: This gene has been demoted to Amber until further evidence is provided. This gene is currently Amber on the Mitochondrial disorders panel (code 112, Version 1.132) - further evidence needs to be submitted to support promoting this gene family member to Green.

Created: 29 Mar 2019, 11:43 a.m.

I don't know

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 2 Dec 2019, 3:58 p.m. | Last Modified: 2 Dec 2019, 3:58 p.m.

Panel Version: 0.16

Initial gene list and info collated by Carl Fratter (Oxford University Hospitals NHS Trust) January 2019 on behalf of the GMS Mitochondrial specialist test group. Gene Symbol submitted: NDUFA4; Suggested intial gene rating: Green; Information provided: Mode of inheritance and publication.

Created: 1 Feb 2019, 4:34 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
No OMIM phenotype

Publications

• 23746447, 29636225

I don't know

Single reported family only, a lot of functional evidence. Does not meet criteria for Green at present.

Created: 31 Aug 2018, 4:15 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 23746447

Green List (high evidence)