Autosomal dominant Riggs-type congenital stationary night blindness with fundus sheen and retinal atrophy due to a novel GNAT1 p.Gln200Arg variant.

PURPOSE: To report an Australian family with congenital stationary night blindness (CSNB, OMIM#139,330) harbouring a novel GNAT1 c.599A > G (p.Gln200Arg) variant. In contrast to previous case reports we observed a fundus sheen, outer retinal changes and electrophysiological features of cone dysfunction in addition to a Riggs-type CSNB.

METHODS

Ophthalmic history, clinical examination and multimodal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT) were obtained. Full-field electroretinography (ERG) was conducted according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards. Genetic testing was performed using a targeted next-generation sequencing panel with familial segregation confirmed by Sanger sequencing. In silico prediction tools and protein structural modelling were used to evaluate the pathogenicity and functional impact of the GNAT1 p.Gln200Arg variant respectively.

RESULTS

Our proband, a 21-year-old transgender male, and his 62-year-old mother had a lifelong history of nyctalopia and visual acuity of 6/6 OU. The mother exhibited a golden sheen, sectoral chorioretinal atrophy and bone spicules. In the proband FAF imaging revealed hypoAF inferiorly with an arc of hyperAF whilst his mother had regions of hypoAF associated with outer retinal atrophy. Full-field electroretinography in the proband showed a cone-isolated retina with normal light-adapted responses. The mother had reduced and delayed light-adapted 30 Hz flicker. Both carried the GNAT1 variant NM_000172.4:c.599A > G (p.Gln200Arg). In silico analysis predicted impaired GTPase activity in Arg200 and constitutively active signally after photoactivation. The c.599A > G variant was classified as likely pathogenic.

CONCLUSIONS

Our study suggests the GNAT1 p.Gln200Arg variant can manifest as both a Riggs-type CSNB and a rod-cone dystrophy within the same pedigree. This work expands the phenotypic spectrum of GNAT1-associated retinopathy and identifies GNAT1 as another potential cause of a fundus sheen.