Phenotypes and genotypes of mitochondrial diseases with mtDNA variations in Chinese children: A multi-center study

• Published in: Mitochondrion 2022-01, Vol.62, p.139-150
• Main Authors: Shi, Yuqing, Chen, Guohong, Sun, Dan, Hu, Chaoping, Liu, Zhimei, Shen, Danmin, Wang, Junling, Song, Tianyu, Zhang, Weihua, Li, Jiuwei, Ren, Xiaotun, Han, Tongli, Ding, Changhong, Wang, Yi, Fang, Fang
• Format: Article
• Language: English
• Subjects: Asians - genetics; Child; China - epidemiology; Cohort Studies; DNA, Mitochondrial - genetics; Female; Genetic Predisposition to Disease; Genotype; Genotypes; Heteroplasmy; Humans; Male; Mitochondria - genetics; Mitochondrial diseases; Mitochondrial Diseases - genetics; Mitochondrial DNA; Mutation; Phenotype; Phenotypes; Point Mutation; Retrospective Studies
• ISSN: 1567-7249; 1872-8278
• DOI: 10.1016/j.mito.2021.11.006

•96%-point mutations (30 alleles in 11 genes) and 4%-deletions were identified as the cause of 14 phenotypes in 262 patients of children with MDs caused by pathogenic mtDNA variants. To our knowledge, this is the largest multi-center study focused on mtDNA variations systematically.•We delineated the genotype and phenotype spectrum and their correlation of mtDNA-associated MDs.•For a suspected MELAS, m.3243A > G mutation is recommended to detect first in both blood and urine. For a suspected LS in clinical, trios-WES and mtDNA genome sequencing by NGS both in blood and urine are recommended first.•We highlight avoiding overdiagnosis and overtreatment through rigorous assessment of pathogenicity. Mitochondrial DNA (mtDNA) associated mitochondrial diseases hold a crucial position but comprehensive and systematic studies are relatively rare. Among the 262 patients of four children’s hospitals in China, 96%-point mutations (30 alleles in 11 genes encoding tRNA, rRNA, Complex I and V) and 4%-deletions (seven of ten had not been reported before) were identified as the cause of 14 phenotypes. MILS presented the highest genetic heterogeneity, while the m.3243A > G mutation was the only “hotspot” mutation with a wide range of phenotypes. The degrees of heteroplasmy in the leukocytes of MM were higher than MELAS. The heteroplasmy level of patients was higher than that in mild and carrier group, while we found low-level heteroplasmy pathogenic mutations as well. Some homoplasmic variations (e.g., m.9176 T > C mutation) are having high incomplete penetrance. For a suspected MELAS, m.3243A > G mutation was recommended to detect first; while for a suspected LS, trios-WES and mtDNA genome sequencing by NGS were recommended first in both blood and urine.