Título

DOMINANT OPTIC ATROPHY CAUSED BY A MUTATION IN THE WFS1 WOLFRAMIN GENE

Objetivo

Bilateral optic disk pallor and progressive vision loss characterize optic atrophy. The main causes are hereditary, frequently caused by mutations in the OPA1 or OPA3 genes. Here we report the case of two Brazilian sisters, who lost color vision due to optic atrophy, after 40 years of age.

Relato do Caso

There was no other reported affected relative in a family within four generations (four of which, were clinically examined). In the sisters, we detected pallor of the optic disk with ophthalmoscopy and discromatopsy through a color vision test. They had two OPA3 polymorphisms (Sanger sequencing), both unlikely pathogenic. We next sequenced the sister’s exome using the Ion ProtonTM plataform. Among the variants encountered, we excluded all common polymorphisms, as well as those synonymous or exclusive of one of the sisters, ending up with 1663 mutations. To identify those possibly causal, we first selected the variants using three prediction algorithms (Sift, Polyphen, Mutation Taster). Among the original 1663 mutations, 50 were classified pathogenic by all of them. Second, we filtered the original 1663 mutations for those present in genes already listed in the RetNet database. We next merged the lists and found five candidate genes: CDH23, HARS, MFN2, TOPORS and WFS1. Based on the phenotypes associated with unfiltered sequencing results, we confirmed these by using the Exomyser software. Besides optic atrophy, the sisters presented with neurogenic bladder, anxiety, hyperactivity and hypoglycemia episodes, symptoms that resemble a mild form of Wolfram-like syndrome

Conclusão

Thus, we suspect three WFS1 mutations cause this rare phenotype: one frameshift in exon 4 and two missense in exon 8. We will perform sequence-specific PCR to haplotype them in both sisters and eventually in other family members. If confirmed, this would be the first report of wedge-shaped optic-disk excavation caused by mutations in the WFS1 gene. This report clarifies the value of exome sequencing when it comes to identify the genetic cause of rare ophtalmologic diseases