title: A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest.
abstract: Assigning a pathogenic role 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 phylogeny-based 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, 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.
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E.Orabona 4, 70126, Bari, Italy.|Department of Science and Technologies, University of Sannio, Via Port'Arsa 11, 82100, Benevento, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Santorsola
authors.affiliation: Department of Medical and Surgical Sciences, Medical Genetics, University of Bologna Medical School, via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Calabrese
authors.affiliation: Department of Medical and Surgical Sciences, Medical Genetics, University of Bologna Medical School, via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Girolimetti
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E.Orabona 4, 70126, Bari, Italy.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Diroma
authors.affiliation: Department of Medical and Surgical Sciences, Medical Genetics, University of Bologna Medical School, via Massarenti 9, 40138, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gasparre
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Via E.Orabona 4, 70126, Bari, Italy. marcella.attimonelli@uniba.it.
authors.forename: Marcella
authors.initials: M
authors.lastname: Attimonelli
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000235:genetics; D016384:Consensus Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial