A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest

Mariangela Santorsola, Claudia Calabrese, Giulia Girolimetti, Maria Angela Diroma, Giuseppe Gasparre, Marcella Attimonelli
2015 Human Genetics  
successfully identifying 23 variants including the majority of the known causative ones. The application of the prioritization workflow to cancer datasets allowed to trim down the number of candidate for subsequent functional analyses, unveiling among these a high percentage of somatic variants. Prioritization criteria were implemented in both standalone (http://sourceforge.net/projects/mtoolbox/) and web version (https://mseqdr.org/mtoolbox.php) of MToolBox. Abstract Assigning a pathogenic
more » ... to mitochondrial DNA (mtDNA) variants and unveiling the potential involvement of the mitochondrial genome in diseases are challenging tasks in human medicine. Assuming that rare variants are more likely to be damaging, we designed a phylogenybased prioritization workflow to obtain a reliable pool of candidate variants for further investigations. The prioritization workflow relies on an exhaustive functional annotation through the mtDNA extraction pipeline MToolBox and includes Macro Haplogroup Consensus Sequences to filter out fixed evolutionary variants and report rare or private variants, the nucleotide variability as reported in HmtDB and the disease score based on several predictors of pathogenicity for non-synonymous variants. Cutoffs for both the disease score as well as for the nucleotide variability index were established with the aim to discriminate sequence variants contributing to defective phenotypes. The workflow was validated on mitochondrial sequences from Leber's Hereditary Optic Neuropathy affected individuals, G. Gasparre and M. Attimonelli: co-last authors. Electronic supplementary material The online version of this article (
doi:10.1007/s00439-015-1615-9 pmid:26621530 pmcid:PMC4698288 fatcat:kw7r53h3y5eelocpogm2z63gz4