Severe mitochondrial cardiomyopathy with m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene: A study of large family analysis.

The m.3303C > T variant in the mitochondrial tRNALeu(UUR) gene is a rare cause of mitochondrial cardiomyopathy (MCM). We report a Japanese family with this variant across three generations, demonstrating a wide clinical spectrum ranging from asymptomatic carriers to lethal infantile cardiomyopathy. The proband was a newborn male infant who developed severe hypertrophic obstructive cardiomyopathy, generalized hypotonia, and profound lactic acidosis (43.9 mmol/L) shortly after birth. Despite intensive care, the patient died at 11 days of age due to multiorgan failure. Autopsy revealed diffuse cardiac hypertrophy and abnormal mitochondria. Genetic analysis showed 98% heteroplasmy of the m.3303C > T variant in multiple tissues. Family screening revealed variant loads ranging from 6% to 100% in seven relatives, with clinical manifestations only appearing when the variant load exceeded 90%. One maternal uncle with 100% muscle heteroplasmy died at the age of 7 years from mitochondrial myopathy. Other family members with variant loads below 90% were asymptomatic. This study demonstrates that the m.3303C > T variant exhibited, within this family, an exceptionally high threshold effect, with severe phenotypes manifesting only at very high heteroplasmy levels (>90%), and highlights the importance of family screening for genetic counseling.