Hypertrophic cardiomyopathy

Gene: MT-TI

Green List (high evidence)

PMID: 39639347 Lopes et al 2024 - Used the bioinformatics pipeline, MitoHPC, to call mtDNA variants in 1363 genomes of cardiomyopathy patients from the 100,000 genomes project. 4 patients, all with a diagnosis of hypertrophic cardiomyopathy (HCM), with no previously identified genetic cause, had the m.4300A>G variant identified (0.6% of HCM cases without a diagnosis). No individuals from the control group were found to have this variant.

Created: 8 Dec 2024, 10:41 p.m. | Last Modified: 8 Dec 2024, 10:41 p.m.

Panel Version: 4.19

The rating of this gene was initially updated to green following NHS Genomic Medicine Service approval, but after later review it was demoted to amber again before the panel was signed off for GMS use, with the comment that it would be better to be analysed through the WGS panel R135 Paediatric or syndromic cardiomyopathy. Reviewers also noted that only the m.4300A>G variant should be looked at.

Created: 6 Dec 2024, 6:49 p.m. | Last Modified: 3 Mar 2025, 12:22 p.m.

Panel Version: 4.21

Mode of inheritance
MITOCHONDRIAL

Publications

• 39639347

I don't know

Comment on list classification: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber.

Below is the summary of recommendation from the NHS Genomic Medicine Service:
MT-TI appears to cause a pretty severe early-onset cardiomyopathy often with other mitochondrial features where reported and therefore suggest that it remains as amber on this panel and is better placed as a green rated gene on R135 where it is already green rated.

Created: 19 Feb 2025, 1:11 p.m. | Last Modified: 19 Feb 2025, 1:11 p.m.

Panel Version: 4.21

Comment on list classification: There are at least four unrelated cases with hypertrophic cardiomyopathy and hence this gene can be promoted to green rating in the next GMS review.

Created: 22 May 2024, 3 p.m. | Last Modified: 22 May 2024, 3 p.m.

Panel Version: 4.12

PMID:12767666 reported two families with familial hypertrophic cardiomyopathy (HCM), where homoplasmic m.4300A>G variant was identified in the tested patients. The proband from family 1 was reported with left ventricular hypertrophy at 11 months of age, while proband from family 2 was diagnosed with nonobstructive idiopathic HCM at 20 years of age.

PMID:23332932 described morphological, biochemical, and molecular features of hearts from 3 transplanted patients from 2 families that were reported previously in PMID:12767666 and PMID:21945886 (2x m.4300A>G, 1x m.4277C>T) with HCM. The age of diagnosis of the patient from PMID:21945886 was 12 years, who showed progressive hearing impairment at the age of 2 years.

PMID:29481798 reported a Tunisian family with healthy parents and five children with clinical features suggestive of dilated cardiomyopathy (DCM). Two of the patients had severe phenotype and the age of diagnosis was one month and at birth for these patients and died at 40 days and 7 days respectively. The other three patients died at early age without diagnosis. The homoplasmic m.4318-4322delC deletion variant was identified in the two patients and their month, while absent in other family members.

PMID:30025578 reported a study on 58 unrelated patients with HCM, where one family was reported with m.4300A>G variant.

Created: 22 May 2024, 2:58 p.m. | Last Modified: 22 May 2024, 2:58 p.m.

Panel Version: 4.9

Mode of inheritance
MITOCHONDRIAL

Phenotypes
familial hypertrophic cardiomyopathy, MONDO:0024573; familial dilated cardiomyopathy, MONDO:0016333

Publications

• 12767666
• 21945886
• 23332932
• 29481798
• 30025578

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, 11:26 a.m. | Last Modified: 2 Dec 2019, 11:26 a.m.

Panel Version: 1.81

I don't know

Listed on OMIM https://www.omim.org/entry/590045. Associated with HCM in homoplasmic state in Taylor JACC 2003, including functional analysis by northern blot.

Created: 4 Oct 2019, 7:47 a.m. | Last Modified: 4 Oct 2019, 7:47 a.m.

Panel Version: 1.77

Mode of inheritance
MITOCHONDRIAL

Publications

• 12767666

Comment on list classification: After discussion at the NHSE GMS Cardiology Specialist Group meeting call on 25th January 2019, this gene should remain Amber to await more evidence.

Created: 4 Mar 2019, 8:55 p.m.

Comment on list classification: New gene added to this panel after submission from the Oxford Medical Genetics Laboratory. Promoted from Red to Amber due to this new review and to raise in discussion with the NHSE GMS Cardiology specialist group.

Created: 17 Jan 2019, 5:16 p.m.

Green List (high evidence)

Evidence for the literature and the Oxford cohort (mansucript awaiting submission) that this variant might account for up to 1% of HCM.

Created: 17 Jan 2019, 5:06 p.m.

Mode of inheritance
MITOCHONDRIAL

Publications

• Publications supporting role of this gene in HCM - PMID: 12767666
• PMID: 30025578

Variants in this GENE are reported as part of current diagnostic practice