■表征患有遗传性眼病(IED)的大型汉族中国队列中角膜营养不良(CD)患者的遗传景观和突变谱。
■回顾性研究。在这项研究中招募了一个大型IED队列,包括69名临床确诊的CD患者,以及其他类型的眼病患者和健康家庭成员作为对照。在我们的研究中,Target_Eye_792_V2芯片上的792个基因用于筛选所有常见的IED,包括22个CD相关基因。
■我们在一个大型IED队列中的22个CD相关基因上鉴定了2334个不同的高质量变异。总共鉴定出21种不同的致病性或可能的致病性突变。IED队列中的其余2313个变异体没有CD相关致病性的证据.总的来说,81.16%(n=56/69)的CD患者接受了明确的分子诊断,和转化生长因子β诱导蛋白(TGFBI),CHTS6和SLC4A11基因覆盖了91.07、7.14和1.79%的诊断病例,分别。在TGFBI基因中发现了12个不同的疾病相关突变,其中11个以前报道过,一个是新颖的。这些TGFBI突变中的四个(p。D123H,p.M502V,p.P501T,在进行临床变异解释后,在我们的汉族IED队列中,p.P501A)被重新定义为可能是良性的。这四个TGFBI突变在无症状个体中检测到,但在CD患者中未检测到,尤其是先前报道的致病突变p.P501T。在56例检测到突变阳性的CD患者中,复发的TGFBI突变是p.R124H,p.R555W,p.R124C,p.R555Q,和p.R124L,占比分别为32.14,19.64,14.29,10.71,3.57%,分别。在28个个体中检测到12个不同的CHTS6致病性或可能致病性突变。复发突变为p.Y358H,p.R140X,和p.R205W,比例分别为25.00,21.43,14.29%,分别。所有与TGFBI相关的个体均为错义突变;与CHTS6突变相关的74.19%为错义突变,25.81%为无义突变。热点区域位于TGFBI个体的外显子4和12中,位于CHTS6个体的外显子3中。没有鉴定出从头突变。
■第一次,我们的大型队列研究系统地描述了22个CD相关基因的变异谱,并评估了IED队列中所有2334种不同的高质量变异的频率和致病性.我们的研究将为东亚和其他人群提供汉族人群特定水平的基线数据。
OBJECTIVE: To characterize the genetic landscape and mutation spectrum of patients with corneal dystrophies (CDs) in a large Han ethnic Chinese Cohort with inherited eye diseases (IEDs).
METHODS: Retrospective study. A large IED cohort was recruited in this study, including 69 clinically diagnosed CD patients, as well as other types of eye diseases patients and healthy family members as controls. The 792 genes on the Target_Eye_792_V2 chip were used to screen all common IEDs in our studies, including 22 CD-related genes.
RESULTS: We identified 2334 distinct high-quality variants on 22 CD-related genes in a large IEDs cohort. A total of 21 distinct pathogenic or likely pathogenic mutations were identified, and the remaining 2313 variants in our IED cohort had no evidence of CD-related pathogenicity. Overall, 81.16% (n = 56/69) of CD patients received definite molecular diagnoses, and transforming growth factor-beta-induced protein (TGFBI), CHTS6, and SLC4A11 genes covered 91.07, 7.14, and 1.79% of the diagnosed cases, respectively. Twelve distinct disease-associated mutations in the TGFBI gene were identified, 11 of which were previously reported and one is novel. Four of these TGFBI mutations (p.D123H, p.M502V, p.P501T, and p.P501A) were redefined as likely benign in our Han ethnic Chinese IED cohort after performing clinical variant interpretation. These four TGFBI mutations were detected in asymptomatic individuals but not in CD patients, especially the previously reported disease-causing mutation p.P501T. Among 56 CD patients with positive detected mutations, the recurrent TGFBI mutations were p.R124H, p.R555W, p.R124C, p.R555Q, and p.R124L, and the proportions were 32.14, 19.64, 14.29, 10.71, and 3.57%, respectively. Twelve distinct pathogenic or likely pathogenic mutations of CHTS6 were detected in 28 individuals. The recurrent mutations were p.Y358H, p.R140X, and p.R205W, and the proportions were 25.00, 21.43, and 14.29%, respectively. All individuals associated with TGFBI were missense mutations; 74.19% associated with CHTS6 mutations were missense mutations, and 25.81% were non-sense mutations. Hot regions were located in exons 4 and 12 of TGFBI individuals and located in exon 3 of CHTS6 individuals. No de novo mutations were identified.
CONCLUSIONS: For the first time, our large cohort study systematically described the variation spectrum of 22 CD-related genes and evaluated the frequency and pathogenicity of all 2334 distinct high-quality variants in our IED cohort. Our research will provide East Asia and other populations with baseline data from a Han ethnic population-specific level.