We aimed to unravel the molecular genetic basis of inherited retinal degeneration (IRD) in a comprehensive cohort of patients diagnosed in the largest center for IRD in Germany. A cohort of 2,158 affected patients from 1,785 families diagnosed with IRD was analyzed by targeted next‐generation sequencing (NGS). Patients with single‐gene disorders (i.e., choroideremia and retinoschisis) were analyzed by Sanger sequencing and multiplex ligation‐dependent probe amplification. Our study cohort accounts for ∼7% of the estimated 30,000 patients with IRD in Germany, thereby providing representative data for both the prevalence of IRDs and the mutation spectrum of IRD genes for the population in Germany. We achieved a molecular diagnostic rate of 35–95%, depending on the clinical entities, with a high detection rate for achromatopsia, retinoschisis, and choroideremia, and a low detection rate for central areolar choroidal dystrophy and macular dystrophy. A total of 1,161 distinct variants were identified, including 501 novel variants, reaffirming the known vast genetic heterogeneity of IRD in a mainly outbred European population. This study demonstrates the clinical utility of panel‐based NGS in a large and highly heterogeneous cohort from an outbred population and for the first time gives a comprehensive representation of the genetic landscape of IRDs in Germany. The data are valuable and crucial for the scientific community and healthcare providers, but also for the pharmaceutical industry in the progressing field of personalized medicine and gene therapy.

Given the overall slow rate of VA loss, VA is unlikely to be a sensitive outcome measure for treatment trials of Stargardt disease. However, given the faster decline in younger patients and those with no or mild visual impairment, VA may be a potential outcome measure for trials targeting such subgroups of patients. These observations will need to be assessed in a prospective study bearing in mind the inherent limitations of retrospective datasets.

No abstract

BackgroundVoretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue.MethodsSeven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months.ResultsAll except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R2>0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R2=0.5).ConclusionsThe presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function.

In summary, we can report that most of our ALMS patients primarily presented with nystagmus and severe photophobia since early childhood interestingly without night blindness in the absence of systemic symptoms. Only genetic testing analysing both nonsyndromic retinal disease (RD) genes and syndromic ciliopathy genes by comprehensive panel sequencing can result in the correct diagnosis, genetically and clinically, with important implication for the physical health of the individual.

No abstract

No abstract

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.