Toward a mtDNA locus-specific mutation database using the LOVD platform

Abstract

ABSTRACT:The Human Variome Project (HVP) is a global effort to collect and curate all human genetic variation affecting health. Mutations of mitochondrial DNA (mtDNA) are an important cause of neurogenetic disease in humans; however, identification of the pathogenic mutations responsible can be problematic. In this article, we provide explanations as to why and suggest how such difficulties might be overcome. We put forward a case in support of a new Locus Specific Mutation Database (LSDB) implemented using the Leiden Open-source Variation Database (LOVD) system that will not only list primary mutations, but also present the evidence supporting their role in disease. Critically, we feel that this new database should have the capacity to store information on the observed phenotypes alongside the genetic varia-

Transition to Next Generation Analysis of the Whole Mitochondrial Genome: A Summary of Molecular Defects

“…mtDB and mtSNP are public databases for mtDNA variations in the presumably general population, but they are static records and some apparently rare changes may simply be due to the underrepresentation of particular ethnic groups. Currently, global collaborative efforts are underway towards a mtDNA mutation database using the Leiden Open‐source Variation Database (LOVD) system, which will greatly enhance our understanding of mtDNA variations and facilitate the interpretation of rare mtDNA variants [Elson et al., ].…”

“…We are in the midst of a transition process from Sanger sequencing to NGS‐based molecular diagnosis of mtDNA disorders. Although sequencing of the whole mitochondrial genome is technically straightforward either by Sanger or NGS, interpretation of the clinical significance of rare variants is challenging because of the highly polymorphic nature of mtDNA and the lack of a comprehensive, up‐to‐date, and clinically annotated database [Elson et al., ]. Our diagnostic laboratory has screened close to 10,000 patients with suspected mitochondrial diseases and characterized the entire mitochondrial genome in over 3,000 probands, by conventional Sanger sequencing or NGS‐based analyses.…”

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation

“…LOVD aggregates data from individual locus-specific databases that use the Leiden open-source variation database system (Fokkema, den Dunnen, & Taschner, 2005). Although initially begun as a means to collect mtDNA pathogenic variants in a manner that includes genotype and phenotypic information (Elson et al, 2012;Shamnamol, Jalali, Scaria, & Bhardwaj, 2013), the function of this database has largely been replaced by MSeqDR that remains actively curated with the support of the United Mitochondrial Disease Foundation (Falk et al, 2015;Shen et al, 2016;Shen, McCormick, Muraresku, Falk, & Gai, 2020). APOGEE, a meta-predictor (Castellana et al, 2017) for variants in protein-coding genes that incorporates predictions from HmtVAR, and MitoTIP (described above), for tRNA variants, are optimized for mtDNA and should be considered when assessing mtDNA variant pathogenicity (see PP3 and BP4 below).…”

Databases for neurogenetics: Introduction, overview, and challenges

“…Mitochondrial cytopathies represent another group of disorders often manifesting at the level of the nervous system and posing a challenge for database curators, as reviewed by Elson et al (2012).…”