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Petra Liskova, Pavel Diblik, Marketa Tesarova, Lukas Huna, Tomas Honzik, Lubica Dudakova; Rare genetic causes of dominant optic atrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3596.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited optic atrophy is a rare disease caused by mutations in at least 10 genes including OPA1, which accounts for more than half of all the cases with a family history. To date, very few families manifesting dominant optic atrophy (DOA) caused by pathogenic variants in OPA3 or WFS1 have been described. The aim of this study was to identify the genetic cause of disease in a Czech and Slovak family with DOA.
Three affected individuals from each of the two families underwent complex ophthalmic examination. Whole exome sequencing (WES) was performed on the probands. Detected variants were prioritized for genes known to be implicated in retinal pathology. Minor allele frequency as per gnomAD was set to <0.005. Missense variants were assessed by six different sofware tools. The presence of possible pathogenic mutations was confirmed and followed within the families by Sanger sequencing.
Two novel sequence variants that segregated with the disease were identified. Affected members from the Slovak family carried the c.301T>A; p.(Tyr101Asn) mutation in OPA3, which encodes a mitochondrial inner membrane protein. In the Czech family the c.2401G>C; p.(Asp801His) mutation was detected in WFS1, which encodes a transmembrane protein, located primarily in the endoplasmic reticulum. In addition to optic atrophy the OPA3 mutation was also associated with severe myopia in all three affected family members and presenile cataract formation in two of them. All three individuals carrying the WFS1 mutation had also perceptive deafness. These additional clinical findings further supported the pathogenicity of the identified mutations.
Our study expands the spectrum of OPA3 and WFS1 mutations associated with DOA and highlights the importance of additional findings such as hearing loss and presenile cataract for the interpretation of WES data.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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