Incomplete congenital stationary night blindness associated with a novel variant in the CACNA1F gene.

Abstract

Purpose: Incomplete congenital stationary night blindness (icCSNB) is a subtype of inherited, non-progressive retinal diseases. Most cases of icCSNB result from mutations in the X-linked gene CACNA1F. We describe the clinical findings of two male siblings diagnosed with icCSNB, both carrying a novel variant c.4008 + 5G > T in CACNA1F inherited from their mother.

Methods: We carried out a comprehensive ophthalmic assessment, including fundus imaging, optical coherence tomography (OCT) scanning and electroretinography. We performed genetic testing with next generation sequencing, in-silico and functional analyses to further characterise the novel variant.

Results: Two male siblings presented with high myopia and reduced visual acuities  at age three. Examination and OCT demonstrated no significant abnormalities in both siblings. Full-field electroretinogram (ffERG) testing demonstrated markedly reduced amplitude to weak flashes and an electronegative waveform to strong flashes in dark-adapted ERGs, resembling that of icCSNB, leading to its diagnosis in both children. Next generation sequencing in the older sibling identified a novel hemizygous c.4008 + 5G > T variant in CACNA1F. In-silico analysis of this variant predicted that it would disrupt normal splicing of CACNA1F, though it was not possible to confirm this by RNA sequencing. This same variant was found in the younger sibling, as well as in their mother who had normal examination and ffERG findings.

Conclusions: We report a novel CACNA1F variant not previously identified in the literature in three patients. Although functional analyses were unable to confirm pathogenicity of this variant, in-silico tools predicted that its effect is consistent with the pathogenesis of icCSNB. Reporting of this family further widens the genotypic spectrum of icCSNB.