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Genotype-Phenotype correlations in PDE6A associated with arRP shows the range of severity

Researches based in the Centre for Ophthalmology, Eberhard Karls University of Tübingen, Germany, has reported the natural course of disease progression, with respect to central retinal function, among PDE6A-associated Retinitis Pigmentosa (RP).  In reviewing a cohort of patients diagnosed with mutations in the phosphodiesterase 6A (PDE6A) gene, results showed that severity of the disease was correlated with specific mutations and the knowledge on the genotype will be relevant in the assessment of treatment.  Central retinal function, specifically visual acuity, contrast sensitivity, and colour vision, have tracked the correlation of a detailed genotype-–phenotype data and this will be useful on how best interventional trials can support specific patient populations.


As previously outlined, PDE6A-associated arRP is a primary rod disease, leading to typical rod–cone dystrophy presenting with night blindness and progressive visual field loss, but with relatively preserved central vision during the course of the disease. The gene encodes the alpha subunit of the cyclic guanosine monophosphate (cGMP) phosphodiesterase, playing a central role in the rod phototransduction cascade. The gene is located on human chromosome 5q32 and consists of 22 exons spanning approximately 45 to 50 kb.  Dysfunction or loss of the PDE6A protein leads to defective biochemical signalling of light stimuli and dysregulation of cGMP in rod photoreceptor outer segments, triggering apoptotic cell death in rods and secondarily in cones.  In the current study, 44 patients from 10 European countries were included – 26 female and 18 male – with a mean age ± SD, 43 ± 13 years.  The cohort had a confirmed genetic diagnosis of PDE6A-associated arRP and patients underwent comprehensive ophthalmological examinations, including BCVA, contrast sensitivity (CS) and colour vision testing.


Following results, variants were classified according to their pathogenicity (based on American College of Medical Genetics and Genomics guidelines) and the most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although researchers indicated that the latter were younger at baseline. As commented in their paper, central retinal function is an important clinical endpoint in current phase I/II interventional trials targeting photoreceptors in RP and these endpoints will be valuable to assess how phenotypes correlate with genotypes among patient populations.  In the their current study, the researchers commented that, “we argue that the severity of the different disease-causing PDE6A mutations in humans may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest)”. The correlation of genotype to phenotype are likely to provide significant data on how best to design future clinical trials for clinicians and their patients.