Abstract
Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.
Highlights
Human oxidative phosphorylation (OXPHOS) disease has the highest incidence among congenital metabolic disorders characterized by a biochemical respiratory chain complex deficiencies and is thought to occur at a rate of 1 in 5,000 births[1]
We investigated the genes encoded in the nuclear and mitochondrial genomes using comprehensive genomic analysis in 142 patients with mitochondrial respiratory chain complex deficiencies
We identified 3 novel disease-causing mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as well as other disease-causing genes and novel pathogenic mutations in known mitochondrial disease-causing genes
Summary
Human oxidative phosphorylation (OXPHOS) disease has the highest incidence among congenital metabolic disorders characterized by a biochemical respiratory chain complex deficiencies and is thought to occur at a rate of 1 in 5,000 births[1]. No more than 15–30% of pediatric diseases diagnosed as mitochondrial disorders show mitochondrial DNA (mtDNA) abnormalities[2,3]; the remaining cases occur because of defects in genes encoded in the nucleus. A certain amount of nuclear-encoded gene products are present in the mitochondria, and roughly 1,500 are thought to play important roles in mitochondrial function[4,5]. It is difficult to diagnose patients with OXPHOS disease at the molecular level because of the massive numbers of potentially involved nuclear genes and genes not yet linked to human disease. Recent studies[6,7] have shown that heterogeneous genetic backgrounds as well as genes previously not linked to mitochondrial functions or localization are associated with this disease. Limitations in target resequencing have motivated us to apply a comprehensive genomic analysis for more accurate molecular diagnosis and for the identification of novel causative genes
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