Seddon Johanna M, De Dikha, Grunenkovaite Laura, Ferrara Daniela
Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States.
Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States.
Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):31. doi: 10.1167/iovs.65.14.31.
The purpose of this study was to define genotypic-phenotypic correlations related to PRPH2-associated retinopathies in an observational longitudinal cohort and to improve diagnostic accuracy.
Individuals with PRPH2 variants were identified by genetic sequencing of 263 individuals (including 59 families). Ocular examinations with multimodal imaging were evaluated.
Two pathogenic/likely pathogenic PRPH2 variants were identified in 22 individuals with retinopathies, low genetic susceptibility to age-related macular degeneration (AMD) and younger age of onset. The mean follow-up was 14 years. One family and 4 independent cases (n = 7) were heterozygous for the variant rs121918563 L185P (p.Leu185Pro). The individuals developed retinopathy compatible with autosomal dominant pattern dystrophy (PD), including adult-onset vitelliform macular dystrophy and butterfly macular dystrophy in their fourth to fifth decades of life, evolving to retinal pigment epithelial (RPE) irregularities and central macular atrophy 20 years later. Two families and an independent case (n = 15) had the rs281865373 splice-site variant c.828+3A>T (IVS2+3A>T) presenting as retinal flecks consistent with adult-onset fundus flavimaculatus with macular dystrophy and diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life progressing to extensive atrophy in the sixth to eighth decades. The L185P variant was associated with better visual acuity (VA) during follow-up versus c.828+3A>T variant. Some individuals were initially misdiagnosed with geographic atrophy secondary to AMD.
Individuals with the L185P variant had less severe disease with clinical manifestation typical of PD and better VA. More advanced disease with CACD and worse VA were associated with the c.828+3A>T variant. Results contribute to knowledge about genotypic-phenotypic associations of PRPH2 retinopathies and inform clinical and therapeutic end points.
本研究旨在确定观察性纵向队列中与PRPH2相关视网膜病变相关的基因型-表型相关性，并提高诊断准确性。
通过对263名个体（包括59个家系）进行基因测序，确定携带PRPH2变异的个体。对其进行多模态成像的眼部检查并评估。
在22名患有视网膜病变、对年龄相关性黄斑变性（AMD）遗传易感性低且发病年龄较轻的个体中，鉴定出两个致病性/可能致病性PRPH2变异。平均随访时间为14年。一个家系和4例独立病例（n = 7）对变异rs121918563 L185P（p.Leu185Pro）呈杂合状态。这些个体发生了与常染色体显性模式营养不良（PD）相符的视网膜病变，包括在其生命的第四至第五个十年出现成人发病的卵黄样黄斑营养不良和蝴蝶状黄斑营养不良，20年后发展为视网膜色素上皮（RPE）不规则和中心黄斑萎缩。两个家系和1例独立病例（n = 15）携带rs281865373剪接位点变异c.828+3A>T（IVS2+3A>T），表现为与成人发病的黄斑营养不良性眼底黄色斑点一致的视网膜斑点，以及与中心性晕轮状脉络膜视网膜营养不良（CACD）相符的弥漫性RPE萎缩，在生命的第五个十年进展为第六至第八个十年的广泛萎缩。与c.828+3A>T变异相比，L185P变异在随访期间与更好的视力（VA）相关。一些个体最初被误诊为继发于AMD的地图状萎缩。
携带L185P变异的个体疾病严重程度较低，具有典型的PD临床表现和较好的VA。与CACD相关的更晚期疾病和较差的VA与c.828+3A>T变异相关。研究结果有助于了解PRPH2视网膜病变的基因型-表型关联，并为临床和治疗终点提供信息。
