title: An integrated approach for classifying mitochondrial DNA variants: one clinical diagnostic laboratory's experience.
abstract: OBJECTIVE
  The mitochondrial genome is highly polymorphic. A unique feature of deleterious mitochondrial DNA (mtDNA) mutations is heteroplasmy. Genetic background and variable penetrance also play roles in the pathogenicity for a mtDNA variant. Clinicians are increasingly interested in requesting mtDNA testing. However, interpretation of uncharacterized mtDNA variants is a great challenge. We suggest a stepwise interpretation procedure for clinical service.
  
  
  METHODS
  We describe the algorithms used to interpret novel and rare mtDNA variants. mtDNA databases and in silico predictive algorithms are used to evaluate the pathogenic potential of novel and/or rare mtDNA variants.
  
  
  RESULTS
  mtDNA variants can be classified into three categories: benign variants, unclassified variants, and deleterious mutations based on database search and in silico prediction. Targeted DNA sequence analysis of matrilineal relatives, heteroplasmy quantification, and functional studies are useful to classify mtDNA variants.
  
  
  CONCLUSIONS
  Clinical significance of a novel or rare variant is critical in the diagnosis of the disease and counseling of the family. Based on the results from clinical, biochemical, and molecular genetic studies of multiple family members, proper interpretation of mtDNA variants is important for clinical laboratories and for patient care.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Eric S
authors.initials: ES
authors.lastname: Schmitt
authors.forename: Megan L
authors.initials: ML
authors.lastname: Landsverk
authors.forename: Victor Wei
authors.initials: VW
authors.lastname: Zhang
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Li
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Lee-Jun C
authors.initials: LJ
authors.lastname: Wong
mesh_terms: D000465:Algorithms; D004272:DNA, Mitochondrial / Q000032:analysis / Q000145:classification* / Q000235:genetics*; D030561:Databases, Nucleic Acid; D004501:Education, Medical; D006801:Humans; D057182:Mendelian Randomization Analysis; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D039781:PubMed; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D004272:DNA, Mitochondrial