Cone Dystrophy with Supernormal Rod Response Novel KCNV2 Mutations in an Underdiagnosed Phenotype
Cone Dystrophy with Supernormal Rod Response Novel KCNV2 Mutations in an Underdiagnosed Phenotype
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DOI：
10.1016/j.ophtha.2013.03.031
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发表时间：
2013-11-01
期刊：
影响因子：
13.7
通讯作者：
Banin, Eyal
中科院分区：
文献类型：
--
作者：
Zelinger, Lina;Wissinger, Bernd;Banin, Eyal
目的：研究以色列人群中视锥细胞营养不良伴超常视杆细胞反应 (CDSRR) 的临床变异和 KCNV2 突变谱。设计：病例系列。参与者：包括视锥细胞为主的疾病患者和未受影响的亲属。该方案经机构审查委员会批准，并获得所有参与者的知情同意。方法：提取基因组DNA并对聚合酶链式反应产物进行Sanger测序。使用 Affymetrix (Santa Clara, CA) 平台进行全基因组单核苷酸多态性分析。主要结果指标：单核苷酸多态性微阵列和纯合性分析、DNA 序列分析、视功能测试和视网膜电图。结果：为了研究以色列和巴勒斯坦人群遗传性视网膜变性的遗传学，我们招募了 220 例锥体为主疾病的指标病例，其中 2 例具有临床诊断CDSRR 的。 KCNV2突变筛查显示1个家系的2个患病姐妹存在2个复合杂合突变，另一个家系有1个纯合突变。为了询问 KCNV2 是否是其余锥体主导疾病患者的致病原因，我们在 52 个近亲家族（最初 220 个）中进行了全基因组纯合性作图，其中 2 个家族具有包含 KCNV2 的纯合区域。突变分析显示每个家族都有不同的纯合突变。此外，在 4 个家系中对 KCNV2 进行了筛查，其中临床数据的审查表明 CDSRR 误诊。分析发现1个家族中有2个复合杂合突变。经过基因分析和临床结果审查后，所有 KCNV2 突变患者的诊断均修订为 CDSRR。 13 名 KCNV2 患者的临床数据表明，尽管在某些病例中存在 CDSRR 的经典表型，但其他病例可能具有正常范围内的暗适应视网膜电图反应。暗适应反应的延迟可能是一个更可靠的指标。结论：这是以色列人群中 CDSRR 遗传和临床分析的第一份报告，导致鉴定出 4 种新的 KCNV2 突变。我们的结果支持最近的研究表明 CDSRR 可能被误诊，因此应考虑对患有局限性疾病的患者进行 KCNV2 突变筛查，特别是当暗适应反应延迟时。 (C) 2013 年由美国眼科学会颁发。
Objective: To study the clinical variability and KCNV2 mutation spectrum in cone dystrophy with supernormal rod response (CDSRR) in the Israeli population.Design: Case series.Participants: Patients with cone-dominated diseases and unaffected relatives were included. The protocol was approved by the institutional review board and informed consent was obtained from all participants.Methods: Genomic DNA was extracted and Sanger sequencing was performed on polymerase chain reaction products. Whole genome single nucleotide polymorphism analysis was performed using Affymetrix (Santa Clara, CA) platforms.Main Outcome Measures: Single nucleotide polymorphism microarray and homozygosity analysis, DNA sequence analysis, visual function testing, and electroretinography.Results: Aiming to study the genetics of inherited retinal degenerations in the Israeli and Palestinian populations, we recruited 220 index cases with cone-dominated diseases, of which 2 carried the clinical diagnosis of CDSRR. Mutation screening ofKCNV2 revealed 2compound heterozygous mutations in 2 affected sisters in 1 family and a homozygous mutation in the other family. Inquiring whether KCNV2 is the cause of disease in the remaining patients with cone-dominated diseases, we performed whole genome homozygosity mapping in 52 consanguineous families (of the initial 220), 2 of which had homozygous regions encompassing KCNV2. Mutation analysis revealed a different homozygous mutation in each family. In addition, KCNV2 was screened in 4 families in which review of the clinical data suggested CDSRR misdiagnosis. The analysis revealed 2 compound heterozygous mutations in 1 family. After the genetic analysis and the review of the clinical findings, the diagnosis was revised to CDSRR in all patients with KCNV2 mutations. Clinical data of 13 KCNV2 patients suggested that, although in some cases the classic phenotype ofCDSRRwas present, others may have dark-adapted electroretinographic responses that are within normal range. The delay in dark-adapted responses may be a more reliable indicator.Conclusions: This is the first report of genetic and clinical analysis of CDSRR in the Israeli population leading to the identification of 4 novel KCNV2 mutations. Our results support recent studies showing that CDSRR can be misdiagnosed, and therefore screening of KCNV2 for mutations should be considered in patients with conedominated diseases, particularly when dark-adapted responses are delayed. (C) 2013 by the American Academy of Ophthalmology.