Leber先天性黑蒙(LCA)是最严重的视网膜病变形式,锥/锥-杆营养不良(CORD)是遗传性视网膜病变的常见形式。GUCY2D的变异构成了LCA和常染色体显性染色体(ADCORD)的最常见原因。这项研究的目的是揭示GUCY2D相关视网膜病变患者的新变体和文献相关表型。52种潜在致病性变异(PPV),包括12部小说(p。Gly144_Ala164del,p.Trp154Glyfs*12,p.Leu186Pro,p.Ala207Pro,p.Ala229Asp,p.Ala353Glu,p.Trp372*,p.Arg528*,p.Arg660Pro,p.Ile682Thr,p.Trp788Cys,和c.1026+171_*486del),在16个ADCORD家庭和34个常染色体隐性遗传LCA(ARLCA)家庭中发现。新的变体c.1026171_*486del是涉及GUCY2D外显子4-20的大规模(16.3kb)缺失,并且在ARLCA家族中被鉴定为杂合状态,模拟纯合p.Trp788Cys变体。在检测到的52个PPV中,32(61.5%)是错误的,七个(13.5%)是剪接,六个(11.5%)是胡说八道,四个(7.7%)是框架内的indel,3例(5.8%)为移码缺失。27例ADCORD患者的中位检查年龄为21.0岁(范围3-54),中位视力(VA)为0.10(范围0.02-0.90)。有48.0%的患者患有黄斑萎缩,86.4%的锥面反应严重减少或熄灭,77.3%,棒反应正常或轻度降低,60.9%患有高度近视。视力障碍,黄斑营养不良,视锥功能障碍随着年龄的增长而恶化。34例ARLCA患者的中位检查年龄为1.1岁(范围为0.3-25)。有55.9%的患者有粗动眼球震颤,68.2%的VA比手部运动差,59.4%的眼底几乎正常,90.6%,具有熄灭的杆和锥响应,高度远视占50.0%。在结论中,在GUCY2D中鉴定出12个新的PPV(包括一个新的大规模缺失)。大多数(32/52,61.5%)的致病GUCY2D变异是错义的。黄斑萎缩的进行性发展,锥体功能障碍,视力障碍,和近视是GUCY2D相关ADCORD的四个主要特征。正常眼底,巡回眼球震颤,早期远视和远视是GUCY2D相关ARLCA特有的常见发现。这项研究中获得的数据将对咨询患者和设计未来的治疗方法具有价值。
Leber congenital amaurosis (LCA) is the most severe form of retinopathy and cone/cone-rod dystrophy (CORD) is a common form of inherited retinopathy. Variants in GUCY2D constitute the most common cause of LCA and autosomal dominant CORD (ADCORD). The purpose of this study was to reveal novel variants and document associated phenotypes of patients with GUCY2D-associated retinopathy. Fifty-two potentially pathogenic variants (PPVs), including 12 novel ones (p.Gly144_Ala164del, p.Trp154Glyfs*12, p.Leu186Pro, p.Ala207Pro, p.Ala229Asp, p.Ala353Glu, p.Trp372*, p.Arg528*, p.Arg660Pro, p.Ile682Thr, p.Trp788Cys, and c.1026 + 171_*486del), were identified in 16 families with ADCORD and 34 families with autosomal recessive LCA (ARLCA). The novel variant c.1026 + 171_*486del is a large-scale (16.3 kb) deletion involving exons 4-20 of GUCY2D, and was identified in an ARLCA family in heterozygous status mimicking a homozygous p.Trp788Cys variant. Among the detected 52 PPVs, 32 (61.5%) were missense, seven (13.5%) were splicing, six (11.5%) were nonsense, four (7.7%) were inframe indel, and three (5.8%) were frameshift deletion. The median age of examination in 27 patients with ADCORD was 21.0 years (ranges 3-54) with a median visual acuity (VA) of 0.10 (ranges 0.02-0.90). There were 48.0% of patients with macular atrophy, 86.4% with severe reduced or extinguished cone responses, 77.3% with normal or mildly reduced rod responses, and 60.9% with high myopia. Visual impairment, macular dystrophy, and cone dysfunction deteriorated with age. The median age of examination in 34 patients with ARLCA was 1.1 years (ranges 0.3-25). There were 55.9% of patients with roving nystagmus, 68.2% with VA of worse than hand motion, 59.4% with almost normal fundus, 90.6% with extinguished rod and cone responses, and 50.0% with high hyperopia. In conclusions, twelve novel PPVs in GUCY2D (including a novel large-scale deletion) were identified. Most (32/52, 61.5%) of causative GUCY2D variants were missense. Progressive development of macular atrophy, cone dysfunction, visual impairment, and myopia are four major characteristics of GUCY2D-associated ADCORD. Normal fundus, roving nystagmus, and hypermetropia in early age are common findings specific to GUCY2D-associated ARLCA. The obtained data in this study will be of value in counselling patients and designing future therapeutic approaches.