Supplementary Material for: Arg339Gln is a Recurrent Variant in Rare Combined Oxidative Phosphorylation Deficiency 4: A New Patient with Biallelic TUFM Gene Variant

Introduction: Combined oxidative phosphorylation deficiency 4 (COXPD4, OMIM#610678) is a very rare mitochondrial disorder caused by biallelic variants in TUFM gene. The condition is characterized by microcephaly, severe early-onset lactic acidosis, and progressive, often fatal, infantile encephalopathy. To date, only eight patients with biallelic TUFM variants have been reported. Case Presentation: We present a case of a female infant with microcephaly who died from severe lactic acidosis at 7 months of age. Genetic analysis revealed homozygous c.1016G>A (p.Arg339Gln) variant in the TUFM gene, which has previously been reported in three other COXPD4 cases. This is the fourth publication describing the same variant in this rare disorder, suggesting that it is a recurrent variant in COXPD4 patients. Conclusion: Arg339Gln variant was found in all COXPD4 patients from Turkey and is considered a potential founder mutation. This report aims to contribute to the phenotypic spectrum of COXPD4, explore the frequency and clinical presentation of the reported variants, enhance the understanding of genotype-phenotype correlations, and raise awareness of rare mitochondrial disorders.