Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing.

Background: Leigh syndrome is a common mitochondrial disorder caused by gene mutations in the nucleus and mitochondria. When building mitochondrial complex I, the main subunit ND1 combines with the Q module to form a 273 kDa complex, which then adds Ndufa3, Ndufa8, and Ndufa13 to create an intermediate product of about 283 kDa called Q/Pp-a. Although Ndufa8 and Ndufa13 have been linked to mitochondrial diseases, the role of Ndufa3 in disease development is still not fully understood.

Methods: A family suspected of having Leigh syndrome was examined. Subjects (two brothers and a sister) underwent brain imaging, and their clinical symptoms were evaluated. Also, whole exome sequencing and minigene testing were performed by examining peripheral blood samples (2 ml) collected from the proband, his parents, and brothers.

Results: Three affected children showed early-onset symptoms, including abnormalities in muscle tone and delayed motor and language development. Symptoms were relatively mild. The second child of the second pregnancy experienced worsened muscle tone abnormalities after injury, slow wound healing, and sustained increased muscle tone up to a year after wound closure. His brain scans revealed lesions in the basal ganglia and brainstem, consistent with Leigh syndrome diagnosis. Genetic analysis identified compound heterozygous mutations in the Ndufa3 gene in all affected family members.

Conclusion: This is the first report of a family affected by Leigh syndrome associated with mutations in the Ndufa3 gene. Our analyses of clinical symptoms, radiological scans, and genetic investigations broaden our understanding of Ndufa3 gene mutations and their role in the development of Leigh syndrome.