MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease

Abstract

MSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the mitochondrial disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal (https://mseqdr.org) integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and disease. MSeqDR-LSDB is a locus specific database that currently manages 178 mitochondrial diseases, 1,363 genes associated with mitochondrial biology or disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar-compliant variant annotations. PhenoTips is used for phenotypic data submission on de-identified patients using human phenotype ontology terminology. Development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources.

MiSynPat: An integrated knowledge base linking clinical, genetic, and structural data for disease-causing mutations in human mitochondrial aminoacyl-tRNA synthetases

“…MiSynPat, by allying sequence data, allelic composition in patients, sequence conservation, structural information, and bibliography, offers a homogeneous resource for in‐depth analyses. The conservation/structural standpoint perfectly complements existing databases, whose main goal is to facilitate genomic investigation (e.g., MSeqDR; Shen et al., ). In addition, the embedded infrastructure and the automated mining and retrieval of literature data with minimal human intervention guarantee durability, regularity and up‐to‐date maintenance of the site.…”

MT-ATP6mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases

“…We ascertained subjects enrolled in the Institutional Review Board‐approved study (#08‐6177) “Metabolic Consequences of Mitochondrial Disease” at the Children's Hospital of Philadelphia (CHOP) or enrolled in the German mitoNET registry who had MT‐ATP6 VUS identified on mtDNA genome sequence performed for suspected mitochondrial disease (Table , n = 16 variants, 14 kindreds, 16 subjects). All variants have been submitted to the Mitochondrial Disease Sequence Data Resource Consortisum (https://mseqdr.org; Shen et al, ). Clinical presentations among carriers of both pathogenic variants and VUS were highly variable, ranging from pediatric‐onset Leigh syndrome, to adult‐onset multisystemic disease.…”

“…The integrated fluororespirometry approach discussed above may be particularly valuable when combined with other approaches that assess CV holocomplex assembly and activity (e.g., blue‐native gel electrophoresis and in‐gel activity analysis). In addition, expert curation of MT‐ATP6 variants will improve understanding and consistency of allele pathogenicity assessment that can be deposited in common community resources including ClinVar and MSeqDR (Shen et al, , ). Indeed, NIH‐supported expert panel curation is currently underway for MT‐ATP6 variants reported to cause pediatric Leigh syndrome (https://projectreporter.nih.gov/project_info_description.cfm?aid=9411950&icde=40411006&ddparam=&ddvalue=&ddsub=&cr=25&csb=default&cs=ASC&pball).…”

HmtDB 2016: data update, a better performing query system and human mitochondrial DNA haplogroup predictor

“…Its website is an innovative international genomic data resource for mitochondrial disease community that facilitates the coherent compilation, organization, annotation and analysis of sequence data from both nuclear and mitochondrial genomes (10,30). The MSeqDR website provides access to a wide range of web-based bioinformatics tools, including the GBrowse instance that enables integrated visualization and analysis of heterogeneous variation and other genomic data contained in optimized annotation tracks.…”