Identification of seven novel ZNF469 mutations in keratoconus patients in a Han Chinese population
Identification of seven novel ZNF469 mutations in keratoconus patients in a Han Chinese population
复制标题
中国汉族圆锥角膜患者中七个新的 ZNF469 突变的鉴定
作者：
Yu Xiaoning;Chen Binbin;Zhang Xin;Shentu Xingchao
目的检测中国汉族散发性圆锥角膜（KC）患者锌指蛋白（ZNF 469）基因的新突变。方法选取53例原发性KC患者、30例高度近视（HM）患者和100例无任何眼部或全身疾病的健康对照者，均为汉族。捐献血样，从外周血白细胞中分离基因组DNA。ZNF 469的序列变异最初在KC患者中用下一代测序鉴定，随后用桑格测序证实。随后在30名HM患者和100名健康对照受试者中筛选KC患者中鉴定的序列变体。在携带ZNF 469突变的KC患者中也筛选了其他与KC相关的基因。使用SIFT程序预测氨基酸取代对ZNF 469蛋白的影响。结果ZNF 469基因编码区存在16种变异。在排除了220名无眼部异常的中国汉族人的全外显子组测序（WES）结果中检测到的5个已知单核苷酸多态性（SNP）、1个假阳性结果和3个突变后，ZNF 469中的7个新突变被发现。2059G>A、c.2137C>A、c.3466G>A、c.3749C>T、c.4300G>A、c.4684G>A和c.7262G>A）。具有c.3466G>A突变的KC患者还显示携带一个胞质分裂贡献因子9（DOCK 9）突变（c.1940C>T）。在HM患者或健康对照组中未检测到突变。KC患者的7个突变均为杂合子。结论ZNF 469基因在中国汉族人群KC中具有致病作用，并扩大了KC的突变谱。
Purpose To test for the potential presence of novel mutations in the zinc finger protein (ZNF469) gene in patients with sporadic keratoconus (KC) from a Han Chinese population. Methods Fifty-three patients with primary KC, 30 patients with high myopia (HM), and 100 unrelated population-matched healthy controls without any ocular or systemic disorders, all of Han Chinese ethnicity, were recruited. Blood samples were donated, and genomic DNA was isolated from peripheral blood leukocytes. Sequence variations in ZNF469 were initially identified in patients with KC with next-generation sequencing and subsequently confirmed using Sanger sequencing. Sequence variants identified in patients with KC were subsequently screened in 30 patients with HM and 100 healthy control subjects. Other genes that were reported to be related to KC were also screened in the patients with KC who carried the mutations in ZNF469. The Sorting Intolerant Form Tolerant (SIFT) program was used to predict the effect of amino acid substitution on the ZNF469 protein. Results Sixteen sequence variants in the coding regions of ZNF469 were identified in this Chinese KC cohort. After five known single nucleotide polymorphisms (SNPs), one false-positive result, and three mutations that were also detected in the results of the whole-exome sequencing (WES) data performed in 220 Han Chinese individuals without ocular abnormalities were removed, seven novel mutations in ZNF469 (c.2059G>A, c.2137C>A, c.3466G>A, c.3749C>T, c.4300G>A, c.4684G>A, and c.7262G>A) that were predicted to be potentially damaging were identified. The patient with KC with the c.3466G>A mutation was also shown to carry one dedicator of cytokinesis 9 (DOCK9) mutation (c.1940C>T). None of the mutations were detected in the patients with HM or the healthy controls. All of the seven mutations in the patients with KC were heterozygote. Conclusions The results suggested for the first time that ZNF469 has a pathogenic role in Chinese patients with KC and have widened the mutation spectrum of KC in the Han Chinese population.
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