Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions

Objectives: This study aimed to investigate the clinical and genetic spectrum in Chinese patients with multiple mtDNA deletions presenting with autosomal-inherited mitochondrial progressive external ophthalmoplegia (PEO). Methods: Long-range polymerase chain reaction and massively parallel sequencing of the mitochondrial genome were performed to detect deletions in muscle mtDNA of 274 unrelated families. Then, targeted next generation sequencing was used to detect nuclear gene variations in patients with multiple mtDNA deletions. Results: A total of 40 Chinese PEO patients (10 males and 30 females) from 20 families were found to have multiple mtDNA deletions in this study, and the median age at onset was 35 (1-70) years. PEO and positive family history were the two prominent features of these patients, and ataxia, neuropathy, and hypogonadism were also present as onset symptoms in some patients. Fifteen of 20 probands with multiple mtDNA deletions were identified to carry nuclear gene variants; eight (40.0%) probands had variants within POLG, two (10.0%) within TWNK, two (10.0%) within RRM2B, two (10.0%) within TK2, and one (5.0%) within POLG2. A total of 24 variants were found in these five nuclear genes, of which 19 were novel. The causal nuclear genetic factors in five pedigrees remain undetermined. Conclusions: The POLG gene is the most common disease-causing gene in this group of PEO patients with multiple mtDNA deletions. While inherited PEO is the most prominent symptoms in these patients, genotypic and phenotypic heterogeneity still exist, for example in onset age, initial symptoms, and accompanying manifestations.