Unique retinal signaling defect in GNB5-related disease.

Abstract

To report a unique retinal signaling defect in GNB5-related disease. A 3-year-old female child underwent detailed systemic and ophthalmological evaluation. The eye examination included fundus photography, spectral domain optical coherence tomography and an extended protocol full-field electroretinography (ERG) including the ISCEV recommended standard steps. The dark-adapted (DA) ERGs were performed to a series of white flashes (range 0.006-30.0cdsm-2) and two red flashes. The DA ERGs to higher stimulus intensities (3.0, 10.0 and 30.0cdsm-2) were tested using a range of inter-stimulus intervals (ISI) of up to 60s. In addition to standard light-adapted (LA) ERGs, a short-duration (0.5s) LA 3.0 30-Hz flicker ERG and a long-duration LA ON-OFF ERG were also performed. Genetic testing included microarray, mitochondrial genome testing and whole exome sequencing. The child was diagnosed to have status epilepticus and bradycardia at 6months of age. Subsequently, she was diagnosed to have global developmental delay and hypotonia. On ophthalmological evaluation, the child fixes and follows light. Fundus evaluation showed mild optic disk pallor; macular SD-OCT was normal. The dim flash DA ERGs (DA 0.006 and DA 0.01cdsm-2) were non-detectable. DA red flash ERGs showed the presence of an x-wave (cone component) and no rod component. The DA 3.0, 10.0 and 30.0 ERGs showed electronegative configuration regardless of the ISI; the averaged a-wave amplitude (4 flashes) was smaller at shorter ISI but became normal at a prolonged ISI (60s). The LA 30-Hz flicker ERG was severely reduced but detectable for the initial 0.5s; this became non-detectable after 5s of averaging. The LA 3.0 2-Hz ERG showed markedly reduced a- and b-wave amplitudes and a reduced b:a ratio; the LA ON-OFF ERGs were non-detectable. WES identified a homozygous null mutation in G protein subunit beta 5 (GNB5; c.1032C>A/p.Tyr344*). This report identifies for the first time a unique retinopathy associated with biallelic mutations in GNB5. The observed phenotype is consistent with a dual retinal signaling defect reminiscent of features of bradyopsia and rod ON-bipolar dysfunction.