College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
BGI-Shenzhen, Shenzhen, China.
Invest Ophthalmol Vis Sci. 2023 Feb 1;64(2):5. doi: 10.1167/iovs.64.2.5.
The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs).
To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing.
All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction.
Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.
本研究旨在描述基于家系的遗传性眼病（IED）队列中基因型-表型的关联和遗传特征的新见解。
为了确定从头突变（DNMs）和遗传特征在 IED 中的作用，我们回顾性分析了一组来自中国的大先证者-父母三系队列。对患者进行了详细检查，并由眼科医生进行临床诊断。对从血液样本中提取的 DNA 进行基于面板的靶向外显子组测序，包含 792 个 IED 致病基因及其侧翼外显子。所有参与者都接受了基因检测。
所有先证者-父母三系均分为 22 个亚组，总体诊断率为 48.67%（605/1243），每个亚组的诊断率从 4%到 94.44%不等。共鉴定出 108 个 IED 致病基因，前 24 个基因解释了 605 个基因解决的三系中 67%的遗传病因。6.76%（84/1243）的三系的遗传病因归因于致病的 DNMs，发病率最高的前 3 个亚组为无虹膜（n = 40%）、马凡综合征/晶状体异位（n = 38.78%）和视网膜母细胞瘤（n = 37.04%）。前 10 个基因在其亚组中的 DNM 诊断率大于 3.5%，包括 PAX6（40.00%）、FBN1（38.78%）、RB1（37.04%）、CRX（10.34%）、CHM（9.09%）、WFS1（8.00%）、RP1L1（5.88%）、RS1（5.26%）、PCDH15（4.00%）和 ABCA4（3.51%）。此外，后代中 DNM 的发生率与父代生殖年龄呈正相关趋势，但与父代（P = 0.154）和母代（P = 0.959）生殖年龄无统计学意义。
基于家系的遗传分析具有较高的准确性和有效性。本研究有助于量化每个基因引起的全谱 IED 的负担，为阐明病因提供了新的潜力，并在遗传咨询和患者管理中发挥了关键作用。
