First submicroscopic inversion of the OPA1 gene identified in dominant optic atrophy - a case report

Dominant optic atrophy (DOA) is an inherited optic neuropathy that mainly affects visual acuity, central visual fields and color vision due to a progressive loss of retinal ganglion cells and their axons that form the optic nerve. Approximately 45-90% of affected individuals with DOA harbor pathogen...

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Bibliographic Details
Published in:BMC medical genetics 2020-11, Vol.21 (1), p.236-6, Article 236
Main Authors: Weisschuh, Nicole, Mazzola, Pascale, Heinrich, Tilman, Haack, Tobias, Wissinger, Bernd, Tonagel, Felix, Kelbsch, Carina
Format: Article
Language:English
Subjects:
Acuity
Adult
Atrophy
Axons
Base Sequence
Breakpoints
Case Report
Case studies
Color vision
Complex rearrangement
Copy number
Deoxyribonucleic acid
Disease
DNA
Dominant optic atrophy
Gene Expression
Gene mapping
Gene mutations
Genetic aspects
Genomes
Genomics
GTP Phosphohydrolases - deficiency
GTP Phosphohydrolases - genetics
Humans
Inversion
Male
Mutation
Non-homologous end joining (NHEJ)
OPA1
Optic atrophy
Optic Atrophy, Autosomal Dominant - diagnosis
Optic Atrophy, Autosomal Dominant - genetics
Optic Atrophy, Autosomal Dominant - pathology
Optic nerve
Optic neuropathy
Retinal ganglion cells
Sequence Inversion
Tomography, Optical Coherence
Whole Genome Sequencing
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Summary:Dominant optic atrophy (DOA) is an inherited optic neuropathy that mainly affects visual acuity, central visual fields and color vision due to a progressive loss of retinal ganglion cells and their axons that form the optic nerve. Approximately 45-90% of affected individuals with DOA harbor pathogenic variants in the OPA1 gene. The mutation spectrum of OPA1 comprises nonsense, canonical and non-canonical splice site, frameshift and missense as well as copy number variants, but intragenic inversions have not been reported so far. We report a 33-year-old male with characteristic clinical features of DOA. Whole-genome sequencing identified a structural variant of 2.4 kb comprising an inversion of 937 bp at the OPA1 locus. Fine mapping of the breakpoints to single nucleotide level revealed that the structural variation was an inversion flanked by two deletions. As this rearrangement inverts the entire first exon of OPA1, it was classified as likely pathogenic. We report the first DOA case harboring an inversion in the OPA1 gene. Our study demonstrates that copy-neutral genomic rearrangements have to be considered as a possible cause of disease in DOA cases.
ISSN:1471-2350
1471-2350
DOI:10.1186/s12881-020-01166-z