Abstract
BackgroundMitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.MethodsWe recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤ 1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines.ResultsSixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n = 3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC.ConclusionsWe confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant, was a founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.
Highlights
Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation
The patients recruited were from 63 non-consanguineous Chinese families, with a positive family history being found in five cases
Muscle biopsy was performed for 40 patients (61%); of these, seven showed an increase in mitochondrial disease criteria (MDC) score after the biopsy sample analysis, but only one patient was re-classified from the probable to the definite MD subgroup
Summary
Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. A consensus statement on the diagnosis and management of MDs was published in 2015 As per this statement, patients suspected to have MDs should undergo clinical evaluation along with biochemical testing of the blood, urine, and cerebrospinal fluid. For investigating mtDNA mutations, deletion, duplication, and depletion, next-generation sequencing (NGS)-based methods were suggested. It stated that muscle or liver samples should be assessed in cases where negative results were obtained with blood samples. Tissue biopsies and subsequent electron transport chain (ETC) enzymology should be performed only when DNA testing cannot provide a diagnosis [6]
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