Abstract
BackgroundThe etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; however, primary mitochondrial disease has been genetically proven in a small subset of patients. The main goal of the present study was to investigate correlations between mitochondrial DNA (mtDNA) changes and alterations of genes associated with mtDNA maintenance or ASD.MethodsSixty patients with ASD and sixty healthy individuals were screened for common mtDNA mutations. Next generation sequencing was performed on patients with major mtDNA deletions (mtdel-ASD) using two gene panels to investigate nuclear genes that are associated with ASD or are responsible for mtDNA maintenance. Cohorts of healthy controls, ASD patients without mtDNA alterations, and patients with mitochondrial disorders (non-ASD) harbouring mtDNA deletions served as comparison groups.ResultsMtDNA deletions were confirmed in 16.6% (10/60) of patients with ASD (mtdel-ASD). In 90% of this mtdel-ASD children we found rare SNVs in ASD-associated genes (one of those was pathogenic). In the intergenomic panel of this cohort one likely pathogenic variant was present. In patients with mitochondrial disease in genes responsible for mtDNA maintenance pathogenic mutations and variants of uncertain significance (VUS) were detected more frequently than those found in patients from the mtdel-ASD or other comparison groups. In healthy controls and in patients without a mtDNA deletion, only VUS were detected in both panel.ConclusionsMtDNA alterations are more common in patients with ASD than in control individuals. MtDNA deletions are not isolated genetic alterations found in ASD; they coexist either with other ASD-associated genetic risk factors or with alterations in genes responsible for intergenomic communication. These findings indicate that mitochondrial dysfunction is not rare in ASD. The occurring mtDNA deletions in ASD may be mostly a consequence of the alterations of the causative culprit genes for autism or genes responsible for mtDNA maintenance, or because of the harmful effect of environmental factors.
Highlights
The etiology of autism spectrum disorders (ASD) is very heterogeneous
Genetic investigation—nuclear deoxyribonucleic acid (DNA) mutation screening of genes responsible for intergenomic communication we focused on those patients with mitochondrial DNA (mtDNA) deletions and performed nuclear DNA mutation screening to investigate genes involved in intergenomic communication
In Patient 8, we found that the mtDNA deletion was accompanied by a heterozygous pathogenic DHCR7 mutation and a rare variant of uncertain significance in NHS actin remodelling activator (NHS)
Summary
The etiology of autism spectrum disorders (ASD) is very heterogeneous. Mitochondrial dysfunction has been described in ASD; primary mitochondrial disease has been genetically proven in a small subset of patients. The number of patients diagnosed with autism spectrum disorders (ASD) has increased with. Mitochondrial disease (MD) is presently one of the most recognized metabolic diseases caused by the failure of both nuclear and/or mitochondrial DNA (mtDNA). MD frequently results in a spectrum of disorders with multisystemic presentations, neurological symptoms are common because tissues with high-energy demands, such as neural tissue, are often the most strongly affected by mitochondrial dysfunction. Primary MD is because of genetic defects in mtDNA or a defect in a nuclear gene that is important for mitochondrial function. These mutations usually affect proteins involved in reactions of oxidative phosphorylation (OXPHOS). In other cases environmental factors, associated disorders or ageing are resulting in secondary alterations
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