Yahya Samar, Smith Claire E L, Poulter James A, McKibbin Martin, Arno Gavin, Ellingford Jamie, Kämpjärvi Kati, Khan Muhammad I, Cremers Frans P M, Hardcastle Alison J, Castle Bruce, Steel David H W, Webster Andrew R, Black Graeme C, El-Asrag Mohammed E, Ali Manir, Toomes Carmel, Inglehearn Chris F
Leeds Institute of Medical Research, University of Leeds, St James's University Hospital, Leeds, United Kingdom; Department of Medical Genetics, School of Medicine, King Abdulaziz University, Rabigh, Saudi Arabia.
Leeds Institute of Medical Research, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
Ophthalmology. 2023 Jan;130(1):68-76. doi: 10.1016/j.ophtha.2022.07.023. Epub 2022 Aug 5.
To characterize the phenotype observed in a case series with macular disease and determine the cause.
Multicenter case series.
Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration.
Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing.
Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients.
All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor.
Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.
对一系列黄斑疾病病例中观察到的表型进行特征描述并确定病因。
多中心病例系列研究。
6个家族（7名患者）患有散发性或多发性黄斑疾病，发病年龄在20至78岁之间，以及1名年龄相关性黄斑变性患者。
患者接受眼科检查、外显子组、基因组或靶向测序，和/或对断点进行聚合酶链反应（PCR）扩增，随后进行克隆和桑格测序或直接桑格测序。
临床表型、基因组研究结果，以及解释这些患者疾病潜在机制的假说。
所有8例患者均携带相同的缺失，该缺失包含TPRX1、CRX和SULT2A1基因，在通过断点PCR筛查的382名对照个体以及通过阵列比较基因组杂交筛查的13096名患有一系列其他遗传疾病的临床遗传学患者中均未发现该缺失。微卫星基因型显示这7个家族没有密切的亲缘关系，但紧邻缺失断点的基因型表明它们可能有一个遥远的共同祖先。
先前的研究发现，单个缺陷CRX等位基因的携带者预计不会产生功能性CRX蛋白，但具有正常的眼部表型。在此，我们表明CRX全基因缺失实际上确实会导致一种显性迟发性黄斑疾病。
