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Session


Keywords: Mitochondria; Neurogenetics; Genotype-phenotype correlations; Massively parallel sequencing; Metabolic disorder

Authors:
Y. Shi; F. Fang; Z. Liu; D. Shen; L. Dai; W. Zhang; J. Li; X. Ren; T. Han; C. Ding

Affiliation: Department of Neurology, Beijing Children's hospital, Capital Medical University, National Center for Children's Health, China, Beijing, Beijing, China


Objective: To delineate the phenotypes and genotypes of children with mitochondrial DNA (mtDNA) variations, and analyze the correlation between them.
Method: The clinical and genetic data of patients with mitochondrial diseases caused by mtDNA variations in the department of Neurology, Beijing Children’s Hospital from Jan 2001 to Feb 2019 was collected retrospectively. Pathogenicity analysis was performed in the three cases with variants of uncertain significance.
Results: There were total 174 diagnosed cases with mtDNA variations collected in our study. Male: Female=1.3:1. The average age of presentation was (5.67±4.07) years old, ranging from the neonatal to 15.1 years old. Twelve phenotypes were discovered in our study, including MELAS (n=82), MILS (n=64), MM (n=6), MERRF (n=5), LHON (n=3), KSS (n=5), MELAS and LS overlap syndrome (n=3), MERRF and LS overlap syndrome (n=2), RIRCD, DEAF, DMDF and Mitochondrial encephalomyopathy with deafness, epilepsy and developmental delay in 1 case respectively.
In our study, there were two kinds of mtDNA variations, including large-single scale deletions and point mutations. The five deletions were all KSS. Among the point mutations, there were 13 genotypes and 29 allele changes. tRNA was the most common. The mutation ratios of Co? were higher than Co? and tRNA.
In MELAS and MELAS/LS, m.3243A>G was the “hot point”, accounting for 92.7%. In MILS and LS/MERRF, MT-ATP6 and m.9176T>C was the most common. MM were all caused by m.3243A>G; MERRF were all caused by m.8344A>G. The most common phenotype of tRNA variations was MELAS. The most common phenotype of Co? variations was MILS. And the only phenotype of Co? variations was MILS. The three cases with variants uncertain significance in our study were respectively m.9396G>A (MELAS), m.3955G>A (MILS), m.10407A>G (Mitochondrial encephalomyopathy with deafness, epilepsy and developmental delay).
Conclusions:
MELAS and MILS were the most common phenotypes, accounting for 83%. tRNA was the most common in which the most common phenotype was MELAS. The most common phenotype of Co? variations was MILS. Moreover, the only phenotype of Co? variations was MILS. In MELAS and MELAS/LS, m.3243A>G was the “hot point”. The mutation threshold was calculated into 35.63%. The most common pathogenic variations of MILS were Co? variations. The most common phenotype and allele change was MT-ATP6 and m.9176T>C, only accounting for 14.1%.