Paediatric or syndromic cardiomyopathy

Gene: MT-TL1

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The reviewers note that cardiomyopathy is not the primary presenting feature. An alternative test is more suitable for syndromic mitochondrial disease: R300 Possible mitochondrial disorder - whole mitochondrial genome sequencing.

Created: 11 Mar 2026, 2:06 p.m. | Last Modified: 11 Mar 2026, 2:06 p.m.

Panel Version: 7.98

Green List (high evidence)

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 m.3243A>G variant.

Expert opinion is sought from the Genomic Medicine Service on the inclusion of this gene on this panel with green raring in the next GMS update.

Created: 24 Jun 2025, 4:46 p.m. | Last Modified: 3 Nov 2025, 5:37 p.m.

Panel Version: 7.92

As per https://www.mitophen.org, there are more than ten different patients reported in peer-reviewed scientific literature with m.3243A>G variant and with hypertrophic cardiomyopathy (HCM) as one of the presenting phenotypes

PMID:7473662 - The m.3243 A > G variant segregated with maternally inherited diabetes mellitus, sensorineural deafness, HCM, or renal failure in a large pedigree of 35 affected members across four generations.

PMID:8477849 - The m.3243 A > G variant was identified in a family suffering from a syndrome with diabetes, deafness and HCMN as main clinical features.

PMID:12874464 - Nine patients with m.3243 A > G variant and prominent kidney disease was reported, of which one had HCM as one of the clinical manifestations.

PMID:14673589 - A 37-year-old male patient was reported with persistent organic personality change as a rare psychiatric manifestation of MELAS syndrome, which was not reported previously. In addition to the core phenotypes of MELAS syndrome and psychiatric manifestations, the patient also presented with cardiac findings, preexcitation syndrome and HCM.

PMID:25639022 - Five patients with psychiatric disturbances were reported with MELAS syndrome, of which four patients harboured m.3243 A > G variant. Two of them presented with HCM among several clinical manifestations.

PMID:30888501 - Retrospectively reviewed 27 MELAS patients from a patient cohort seen at a hospital, of which 13 patients were diagnosed with m.3243 A > G variant. HCM was found in one of them, while wolff parkinson white and congestive heart failure were reported in one each.

PMID:30133155 - Nine unrelated patients were reported with m.3243 A > G variant, of which only three patients met the criteria for MELAS syndrome. HCM was reported in eight of these patients moderate to severe regurgitation of various valves. Electrocardiography (ECG) showed preexcitation pattern with short PR intervals and delta waves (Wolff‐Parkinson‐White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient.

Created: 24 Jun 2025, 3:38 p.m. | Last Modified: 24 Jun 2025, 4:38 p.m.

Panel Version: 5.3

Mode of inheritance
MITOCHONDRIAL

Phenotypes
MELAS syndrome caused by mutation in MTTL1, MONDO:0800032; hypertrophic cardiomyopathy, MONDO:0005045

Publications

• 7473662
• 8477849
• 12874464
• 14673589
• 25639022
• 30888501
• 30133155

Green List (high evidence)

Hypertrophic cardiomyopathy is part of the phenotype for the m.3243A>G 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

• 22513320
• 31403078
• 23355809

Mode of pathogenicity
Other

Red List (low evidence)

No phenotype

Created: 25 Mar 2019, 4:30 p.m.

No evidence

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
Unknown

This gene was suggested by Dr Atsuko Okazaki (Division of Genomic Medicine Research, Medical Genomics Center, National Center for Global Health and Medicine, Tokyo, Japan) to be added to this panel. Comments from Dr Atsuko Okazaki: "Among our ~2000 patients, certain numbers of hypertrophic cardiomyopathy patients have m.3243A>G mutation in MT-TL1 with high heteroplasty rate in the heart. Although reporting mitochondrial DNA mutations with their pathogenicity is always challenging due to the heteroplasty rate in affected organs, I think it might be one possibility to let clinicians know that m.3243A>G is a causative mutation for hypertrophic cardiomyopathy if mutation rate is high in the heart."
Sources: Expert Review

Created: 4 Dec 2018, 11:28 a.m.

Mode of inheritance
MITOCHONDRIAL