Arno Gavin, Hull Sarah, Carss Keren, Dev-Borman Arundhati, Chakarova Christina, Bujakowska Kinga, van den Born L Ingeborgh, Robson Anthony G, Holder Graham E, Michaelides Michel, Cremers Frans P M, Pierce Eric, Raymond F Lucy, Moore Anthony T, Webster Andrew R
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom 4NIHR BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4806-13. doi: 10.1167/iovs.16-19687.
Mutation of RGR, encoding retinal G-protein coupled receptor was originally reported in association with retinal dystrophy in 1999. A single convincing recessive variant segregated perfectly in one family of five affected and two unaffected siblings. At least one further individual, homozygous for the same variant has since been reported. The aim of this report was to reevaluate the findings in consideration of data from a whole genome sequencing (WGS) study of a large cohort of retinal dystrophy families.
Whole genome sequencing was performed on 599 unrelated probands with inherited retinal disease. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging (FAF) and spectral-domain optical coherence tomography (OCT).
Overall we confirmed that affected individuals from six unrelated families were homozygous for both the reported RGR p.Ser66Arg variant and a nearby frameshifting deletion in CDHR1 (p.Ile841Serfs119*). All had generalized rod and cone dysfunction with severe macular involvement. An additional proband was heterozygous for the same CDHR1/RGR haplotype but also carried a second null CDHR1 mutation on a different haplotype. A comparison of the clinical presentation of the probands reported here with other CDHR1-related retinopathy patients shows the phenotypes to be similar in presentation, severity, and rod/cone involvement.
These data suggest that the recessive retinal disorder previously reported to be due to homozygous mutation in RGR is, at least in part, due to variants in CDHR1 and that the true consequences of RGR knock-out on human retinal structure and function are yet to be determined.
编码视网膜G蛋白偶联受体的RGR突变最初于1999年被报道与视网膜营养不良相关。在一个有五个患病和两个未患病兄弟姐妹的家庭中，一个令人信服的隐性变异完美分离。此后至少又报道了一名携带相同变异纯合子的个体。本报告的目的是结合来自一大群视网膜营养不良家庭的全基因组测序（WGS）研究数据，重新评估这些发现。
对599名患有遗传性视网膜疾病的无关先证者进行了全基因组测序。进行了详细的表型分析，包括临床评估、视网膜电图、眼底照相、眼底自发荧光成像（FAF）和光谱域光学相干断层扫描（OCT）。
总体而言，我们证实来自六个无关家庭的患病个体对于报道的RGR p.Ser66Arg变异以及CDHR1中附近的移码缺失（p.Ile841Serfs119*）均为纯合子。所有个体均有广泛的视杆和视锥功能障碍，并伴有严重的黄斑受累。另一名先证者对于相同的CDHR1/RGR单倍型是杂合子，但在不同单倍型上还携带了第二个CDHR1无效突变。将此处报道的先证者的临床表现与其他CDHR1相关视网膜病变患者进行比较，发现表型在表现、严重程度和视杆/视锥受累方面相似。
这些数据表明，先前报道的由RGR纯合突变导致的隐性视网膜疾病至少部分是由于CDHR1中的变异，而RGR基因敲除对人类视网膜结构和功能的真正影响尚待确定。
