A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4


Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.

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We thank the patient’s parents for participating in this study. We are grateful to the medical and nursing staff at the pediatric intensive care unit (PICU), Ruth Rappaport Children’s Hospital, Rambam Health Care Campus for their dedicated work and patient care. Corinne Alban, Department of Genetic and metabolic Diseases Hadassah Medical Center, is acknowledged for technical assistance.

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Correspondence to Hagit Baris Feldman.

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CG-J, SEW, JDO, and ARS are full-time employees of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receive stock options as part of compensation. The remaining authors declare that they have no conflict of interest.

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Hershkovitz, T., Kurolap, A., Gonzaga-Jauregui, C. et al. A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4. J Hum Genet 64, 589–595 (2019). https://doi.org/10.1038/s10038-019-0592-6

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