Identification of AFG3L2 dominant optic atrophy following reanalysis of clinical exome sequencing

Abstract

Purpose: To highlight the importance of the utility of clinical exome sequencing, and show how it led to the diagnosis of nonsyndromic autosomal dominant optic atrophy arising from an autosomal dominant variant in AFG3L2.

Observations: A healthy father and daughter of East African heritage experienced the onset of vision loss in the first decade of life due to optic atrophy. No additional neurologic or neuroimaging abnormalities were detected. Clinical exome sequencing was initially performed and provided a negative result. Reanalysis of the sequencing data revealed an autosomal dominant pathogenic variant in AFG3L2, c.1064C>T (p.Thr355Met), a gene that was recently identified to be associated with non-syndromic optic atrophy. This variant has previously been reported in a patient with optic atrophy, motor disturbances, and an abnormal brain MRI.

Conclusions: As the causes of dominant optic atrophy continue to expand, accurate genetic diagnosis is aided by an iterative reanalysis process for individuals and families when initial exome and genome testing does not provide an answer.

Keywords: AFG3L2 mutation; Dominant optic atrophy; SCA28.

Fig. 1

Optic disc photos in proband (case 1) showing small optic discs with wedge-shaped temporal pallor in both eyes. The nasal optic discs are less severely affected.

Fig. 2

Optic disc photos in father (case 2) showing small optic discs with diffuse pallor, worse temporally, in both eyes.