Abstract
BACKGROUND: The NADH:ubiquinone oxidoreductase complex assembly factor gene (NDUFAF5) has been linked to the occurrence of Leigh syndrome, but few causative mutations have been identified. Here we report a rare case of Leigh syndrome in an infant who died in the early postnatal period. METHODS: We performed whole-exome sequencing (WES) and mutation analysis of NDUFAF5 to obtain genetic data on the patient and describe the clinical and genetic characteristics. RESULTS: The proband was a 2-month-old male infant who suffered from recurrent vomiting and persistent seizure and died at 2 months of age after early medical support and treatment. His parents reported the unexplained death of the infant's older brother at 1 year of age. WES of the patient's DNA revealed c.357C>G and c.611C>T compound heterozygous mutations in NDUFAF5; analysis with the MutationTaster application indicated that both were pathogenic (p = 0.99). Significant structural changes in the transport domain of the protein were predicted using SWISS-MODEL. We estimated the stability of the mutant protein using a mutation cutoff scanning matrix and found reductions in Gibbs free energy (-0.623 kcal/mol for p.D119E and -0.813 kcal/mol for p.A204V), indicating that the mutations led to an unstable protein structure. We speculated that the patient died as a result of impaired mitochondrial function caused by the NDUFAF5 mutations, and made a diagnosis of Leigh syndrome. CONCLUSION: Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype-phenotype map of mitochondrial respiratory chain complex I deficiency.