TMEM43
Details
TMEM43 encodes transmembrane protein 43 and was the first non-desmosomal gene identified to cause ARVC (2008). A single founder missense variant, p.Ser358Leu, is considered definitively pathogenic and is highly prevalent in Newfoundland, Canada, but observed worldwide. TMEM43-cardiomyopathy is one of the most malignant forms of ACM — nearly fully penetrant in males with a very high risk of ventricular arrhythmias and SCD, warranting early consideration of ICD implantation.
Key Facts
- Founder variant: p.Ser358Leu — a definitively pathogenic missense mutation. (sources/ACM-Genotype-Mx-JCE-2024, rating: high)
- Penetrance: Nearly fully penetrant in males. Highly malignant with very high risk of VA and SCD. (sources/ACM-Genotype-Mx-JCE-2024)
- ECG: Poor R-wave progression is more common than precordial T-wave inversions (distinctive feature vs other ACM forms). LV dilatation. (sources/ACM-Genotype-Mx-JCE-2024)
- Exercise: Associated with worse clinical outcomes — exercise restriction warranted. (sources/ACM-Genotype-Mx-JCE-2024)
- Management: Early ICD implantation indicated for at-risk male TMEM43 variant carriers. Should be regarded as a highly malignant disease. (sources/ACM-Genotype-Mx-JCE-2024)
- Prevalence: Great geographical differences — high in Newfoundland (founder effect); low elsewhere. (sources/ACM-Genotype-Mx-JCE-2024)
- Young men are at particularly high risk for severe arrhythmias. (sources/ACM-Genotype-Mx-JCE-2024)
Contradictions / Open Questions
- Data are dominated by the single p.Ser358Leu founder variant — whether other TMEM43 variants cause a similar phenotype is unclear.
- No TMEM43-specific risk calculator exists despite the distinctive natural history.
- Optimal ICD timing in female carriers is less well-defined than in males.
- Whether the near-complete male penetrance reflects biology or ascertainment bias in the Newfoundland founder population is debated.
Connections
- Related to entities/PKP2
- Related to entities/PLN
- Related to entities/DES
- Related to entities/ARVC
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to concepts/Exercise-Restriction-in-ARVC
- Related to sources/ACM-Genotype-Mx-JCE-2024