Exaggerated Status of "Novel" and "Pathogenic" mtDNA Sequence Variants Due to Inadequate Database Searches

Given its relative ease, screening the entire mitochondrial DNA (mtDNA) for heteroplasmic or novel homoplasmic mutations has become part of the routine diagnostic workup for the molecular geneticist confronted with a disease case exhibiting clinical and biochemical features of mitochondrial dysfunction. "Novelty" of a given mtDNA variant is most often equated with nonregistration in the extensive MITOMAP database (www.mitomap.org). This practice has led to a number of spurious findings and wrong conclusions concerning the pathogenic status of specific mtDNA mutations, especially in the absence of proper evaluation and pathogenicity scoring. We demonstrate by way of real cases targeting the mt-tRNA(Cys) (MT-TC) gene and a stretch within the MT-ND3 gene, that a straightforward Google search can identify twice as many previously observed mutations than any MITOMAP query could achieve. Further, we reassess the recent rediscovery of m.15287T>C by listing all known occurrences and, where possible, providing the haplogroup context, shedding new light on the potential pathogenicity status of m.15287T>C.