OPA1: 516 unique variants and 831 patients registered in an updated centralized Variome database

Abstract

Background: The dysfunction of OPA1, a dynamin GTPase involved in mitochondrial fusion, is responsible for a large spectrum of neurological disorders, each of which includes optic neuropathy. The database dedicated to OPA1 ( https://www.lovd.nl/OPA1 ), created in 2005, has now evolved towards a centralized and more reliable database using the Global Variome shared Leiden Open-source Variation Database (LOVD) installation.

Results: The updated OPA1 database, which registers all the patients from our center as well as those reported in the literature, now covers a total of 831 patients: 697 with isolated dominant optic atrophy (DOA), 47 with DOA "plus", and 83 with asymptomatic or unclassified DOA. It comprises 516 unique OPA1 variants, of which more than 80% (414) are considered pathogenic. Full clinical data for 118 patients are documented using the Human Phenotype Ontology, a standard vocabulary for referencing phenotypic abnormalities. Contributors may now make online submissions of phenotypes related to OPA1 mutations, giving clinical and molecular descriptions together with detailed ophthalmological and neurological data, according to an international thesaurus.

Conclusions: The evolution of the OPA1 database towards the LOVD, using unified nomenclature, should ensure its interoperability with other databases and prove useful for molecular diagnoses based on gene-panel sequencing, large-scale mutation statistics, and genotype-phenotype correlations.

Keywords: Database; Dominant optic atrophy; Interoperability; Neurological disorders; OPA1; Sequence variant.

Fig. 1

Sample recording for a given patient in the OPA1 database. a. molecular items (“Variant remarks” line removed to save space); b. screening items; c. individual items; and d. phenotype items. Abbreviations and legends of the fields are given by following the link “Legend” on the web page of each table; “SEQ”: sequencing (Sanger); “M”: male; “(France)”: reported by the laboratory in France; “OD”: oculus dexter (right eye); “OS”: oculus sinister (left eye); “0.7 LogMAR”: best corrected visual acuity 0.7 LogMAR (HP:0030560). “centrocecal”: centrocecal scotoma (HP:0000576); “RNFL two or more”: mean retinal nerve fiber layer thinning in 2 or more quadrants; “MRI”: brain MRI performed; “hemeralopia”: hemeralopia (HP:0012047); “photophobia”: photophobia (HP:0000613). Data as of October 12, 2018

Fig. 2

Distribution of the 516 unique genomic variants in the LOVD OPA1 database (compact view). Eighteen large rearrangements (eleven deletions, six duplications, and one deletion-insertion) are shown as extended bars with rafters, substitutions as black bars, deletions as blue bars, insertions as green bars, and duplications as orange bars. At the top are reported the genomic coordinates on human chromosome 3 (assembly GRCh37/hg19), and OPA1 transcript variants 1 and 8 structure in navy blue with alternative exons in pink, including exon numbering. The full view detailing the names of each mutation is available in Additional file 2. Adapted from UCSC Genome Browser (http://genome.ucsc.edu) with the LOVD OPA1 database custom track; data as of October 12, 2018

Fig. 3

Distribution of the different effects on the protein of the OPA1 variants considered pathogenic. Other consequences (5%) include: synonymous (11), no protein is produced (5), duplication (3), and extension (1). Data as of October 12, 2018

Fig. 4

Tree view of the Human Phenotype Ontology term “Abnormal best corrected visual acuity test” (HP:0030532). In the Ontology Lookup Service [44]. The term is highlighted, superclasses indicated above, subclasses indicated below. Data as of Human Phenotype Ontology (HPO) version 2018-06-13