Paediatric or syndromic cardiomyopathy

Gene: MT-ND5

Red List (low evidence)

I have reviewed the literature for a link between MT-ND5 and cardiomyopathy, and I have included my notes regarding individual papers below. In summary, it seems that a proportion of patients (including paediatric cases) with Leigh disease due to the pathogenic m.13513G>A p.(Asp393Asn) variant have a clinical presentation that includes hypertrophic cardiomyopathy or other cardiac presentations. However, the primary presentation of these individuals includes lactic acidosis, complex 1 deficiency, and other clear signs of mitochondrial disease. Also of note is that, in most of these cases, other genetic causes of cardiomyopathy were not tested for; hence, although plausible, it cannot be definitively concluded that the cardiomyopathy in each case is due to the MT-ND5 variant.

There are a few articles that link other MT-ND5 variants to cardiomyopathy. However, these variants cannot be classified as pathogenic, and indeed, one variant that is claimed to cause isolated HCM (m.12338T>C p.Met1? as described by Liu et al. 2012; PMID: 22759514) appears to be a frequent (and therefore probably benign) polymorphism.

In conclusion, whilst it is generally accepted that cardiomyopathy can be part of the clinical presentation of mitochondrial disease, including Leigh syndrome due to the pathogenic MT-ND5 m.13513G>A p.(Asp393Asn) variant, I can find no good evidence that MT-ND5 variants can cause a clinical phenotype primarily characterised by cardiomyopathy. For this reason, I do not think MT-ND5 should be rated green for, or included in, any cardiomyopathy gene panel (including R131 or R135). I think an amber rating is appropriate.

Genetic testing for mitochondrial disorders (including MT-ND5-related disorders) is already catered for by the R300 (possible mitochondrial disorder – whole mitochondrial genome sequencing) test. I think that any patient that had cardiomyopathy as part of the broader clinical presentation due to m.13513G>A p.(Asp393Asn) should, and would, be appropriately referred for R300. Furthermore, mtDNA is not usually targeted for enrichment by whole exome sequencing-based tests (such as those employed by most cardiac genetic testing services); hence, testing for mitochondrial genes is not technically very feasible for most labs anyway.


m.13513G>A p.(Asp393Asn)

This variant is widely accepted as a class 5 pathogenic variant that causes mitochondrial disorders (e.g. Leigh syndrome, MELAS, LHON).

Kirby et al. (2003; PMID: 14520659): Three individuals with Leigh disease (complex 1 deficiency) were found to have this variant. One of the individuals, 35 years old, with Leigh disease and complex 1 deficiency was noted, a year after presentation, to have HCM ‘for which no other cause was found’. However, there is no indication that this is individual was genetically tested for HCM-related genes.

Bannwarth et al. (2013; PMID: 23847141): Again, one patient suspected of having a mitochondrial disorder due to various clinical features consistent with Leigh syndrome who was found to have this variant was also noted to have HCM. Again, no indication of actually being tested for HCM-related genes.

Na & Lee (2023; PMID: 37318682): They did mtDNA sequencing in 31 patients with clinical features of Leigh syndrome. Four patients found to have this variant at heteroplasmy levels of 55.5-71.6%. All four found to have HCM on echo. No evidence they were tested for HCM-related genes. No other useful evidence.

Brecht et al. (2015; PMID: 25681084): They describe a 12-month-old with “Leigh syndrome caused by the MT-ND5 m.13513G>A mutation presenting with renal salt loss, proximal tubular dysfunction and SIADH in association with rapidly progressive hypertrophic cardiomyopathy, WPW-like conduction defect requiring electrical cardioversion and arterial hypertension, further extending the spectrum of presentation of this mutation.” There is no indication that they tested the baby for any other cardiac genes.

Chol et al. (2003; PMID: 12624137): They describe three unrelated children with complex I deficiency and Leigh syndrome due to this variant. Two of the children had HCM, but this was not the presenting feature. No indication that they were tested for cardiac genes.

Sudo et al. (2004; PMID: 14730434): Screened 84 Japanese patients with Leigh syndrome and six of them had this variant with 42-70% heteroplasmy. 5 of these had cardiac conduction defects including WPW syndrome in three of them. But no cardiomyopathy. No indication that they were tested for cardiac genes.

Shimozawa et al. (2022; PMID: 36104228): This report describes a neonate with IUGR who at 1 day of age had lactic acidosis and severe complex 1 deficiency in fibroblasts. He was also found to have HCM. Whole exome sequencing identified m.13513G>A p.(Asp393Asn) with heteroplasmy of 79% in blood. The mutation was believed to have arisen de novo, as it was not detected in maternal DNA from blood, hair, urine, or nail cells. This paper also include a table that includes details of multiple cases of children with the m.13513G>A p.(Asp393Asn) described in the literature, including any cardiac involvement.


m.12338T>C p.Met1?

Liu et al. (2012; PMID: 22759514): Describes a Han Chinese family with HCM and this variant. A proband, his mother, and two siblings were all affected with HCM (no other mito features), and all of them were found to have this variant. This of course is not surprising that all four matrilineal relatives have the variant. Only mtDNA was screened (no sarcomere gene screen). The variant was not detected in 151 Han Chinese control individuals.

This variant appears to be quite frequent on gnomAD in East Asians. M-12338-T-C (GRCh38): Detected homoplasmic in 37 of 1,482 East Asians and in other populations. I believe it is correctly classified as a benign polymorphism.


m.13651A>C p.(Thr439Pro)

Zhou et al. (2019; PMID: 30587702): a 21-year-old proband presented with limb weakness and some features of a cardiomyopathy. Further investigations in the proband and family were consistent with a mitochondrial myopathy. Exome studies found this variant detected in the proband and in all maternal relatives who were all affected except one. The relatives included a sister, mother, and three maternal aunts. Of note, the proband was the only member of the family with possible cardiomyopathy. Of course, it is no surprise that all maternal relatives had the variant. This variant is classified at Oxford lab as a cold VUS.


m.13805A>C p.( p.(Ala490Gly)

Ayalon et al. (2013; PMID: 23628297): Case study of a man with clinical features of mitochondrial myopathy who also presented with late-onset cardiomyopathy (more like DCM than HCM) was found to have this variant, which I think is just a VUS.


Other mtDNA Variants

Wei et al. (2009; PMID: 19473338): The authors of this paper claim to present evidence that three mtDNA variants, m.7697G>A (not in MT-ND5), m.12477T>C and m.13135G>A (both in MT-ND5) and mitochondrial haplogroup M10 are associated with susceptibility to HCM. These variants are fairly frequent polymorphisms. They present three pedigrees of families with HCM (pedigrees A, B, and C). The obtained results are rather confusing in that maternal relatives in each of these pedigrees appear not to have the same mtDNA variants, which means there are instances of non-segregation of at least one of these variants in each of the pedigrees. There is also a case of apparently paternally transmitted HCM in pedigree A, which is a clear suggestion that the HCM in this pedigree is not caused by a mtDNA variant.

Created: 18 Sep 2025, 9:15 a.m. | Last Modified: 18 Sep 2025, 9:15 a.m.

Panel Version: 7.86

Mode of inheritance
MITOCHONDRIAL

Phenotypes
Leigh syndrome; LHON; MELAS

Publications

• PMID: 14520659
• PMID: 23847141
• PMID: 37318682
• PMID: 25681084
• PMID: 12624137
• PMID: 14730434
• PMID: 36104228
• PMID: 22759514
• PMID: 30587702
• PMID: 23628297
• PMID: 19473338

Green List (high evidence)

After consultation with the clinical team, this gene is tagged for expert review by the Genomic Laboratory Hubs on the inclusion of this gene with green rating on this panel.

Created: 27 Oct 2025, noon | Last Modified: 3 Nov 2025, 5:38 p.m.

Panel Version: 7.92

Comment on list classification: As reviewed by Katherine Schon on R131 Hypertrophic cardiomyopathy panel, HCM is reported as one of the presenting phenotypes in several unrelated patients with variants in MT-ND5 gene.

This gene can therefore be promoted to green rating on the next GMS update.

Created: 25 Jun 2025, 6:15 p.m. | Last Modified: 25 Jun 2025, 6:15 p.m.

Panel Version: 7.4

PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.

Created: 25 Jun 2025, 6:07 p.m. | Last Modified: 9 Oct 2025, 4:47 p.m.

Panel Version: 7.91

Mode of inheritance
MITOCHONDRIAL

Phenotypes
hypertrophic cardiomyopathy, MONDO:0005045

Publications

• 14520659
• 22759514
• 23847141
• 30587702

Green List (high evidence)

Hypertrophic cardiomyopathy has been reported with the c.1315A>G pathogenic variant.

Created: 24 Jun 2025, 10:19 a.m. | Last Modified: 24 Jun 2025, 10:19 a.m.

Panel Version: 5.3

Mode of inheritance
MITOCHONDRIAL

Publications

• 22759514
• 30587702