Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration

BACKGROUND: Age-related macular degeneration (AMD) is a common sight threatening condition. However, there are a number of monogenic macular dystrophies that are clinically similar to AMD, which can potentially provide pathogenetic insights. METHODS: Three siblings from a non-consanguineous Greek-Cypriot family reported central visual disturbance and nyctalopia. The patients had full ophthalmic examinations and color fundus photography, spectral-domain ocular coherence tomography and scanning laser ophthalmoscopy. Targeted polymerase chain reaction (PCR) was performed as a first step to attempt to identify suspected mutations in C1QTNF5 and TIMP3 followed by whole genome sequencing. RESULTS: The three patients were noted to have symptoms of nyctalopia, early paracentral visual field loss and, in older patients, central vision loss. Imaging identified pseudodrusen, retinal atrophy and RPE-Bruch’s membrane separation. Whole genome sequencing of the proband revealed two novel heterozygous variants in C1QTNF5, c.556C>T, and c.569C>G. The mutation segregated with disease in this family, occurred in cis, and resulted in missense amino acid changes P186S and S190W in C1QTNF5. In silico modeling of the variants revealed that the S190W mutations was likely to have the greatest pathologic effect and that the combination of the mutations was likely to have an additive effect. CONCLUSIONS: The novel mutations in C1QTNF5 identified here expand the genotypic spectrum of mutations causing late-onset retinal dystrophy

Multiple evanescent white dot syndrome: clinical course and factors influencing visual acuity recovery

Objective: To report the demographics and the clinical course of patients with multiple evanescent white dot syndrome (MEWDS) and to investigate for those factors which influence visual acuity (VA) recovery. Methods: This is a retrospective single-centre observational study. Electronic medical records and retinal imaging of patients with a diagnosis of MEWDS with a minimum follow-up of 3 months were reviewed. Patients were categorised into three groups according to the VA at presentation and at the last visit: group 1 >0.48 logarithm of the minimum angle of resolution (LogMAR), group 2 640.48 and 650.18 LogMAR and group 3 <0.18 LogMAR. All patients had non-invasive multimodal imaging including optical coherence tomography, near-infrared reflectance imaging and blue fundus autofluorescence at presentation and during follow-up. Results: A total of 51 eyes from 51 patients (41 women, mean age 29.8\ub17.8 years) were included. Significantly more patients presented in the autumn (X2=8.69, p=0.034). The percentage of eyes recovering vision to 0.0 LogMAR or better was 80.3% (41/51). Worse presenting vision and young age at presentation were independent significant predictive variables for poorer final VA (p=0.002 and p=0.02, respectively). No imaging features were significantly predictive of complete versus incomplete recovery, but disc hyperfluorescence on fluorescein angiography was more common in those with incomplete recovery. Conclusions: Although the majority of cases have a benign prognosis, the clinical spectrum of MEWDS includes incomplete visual recovery. In our series, poor presenting VA and young age were associated with poor VA outcome. Further study is warranted to confirm these findings