Eye Research Center, the Five Senses Institute, Iran University of Medical Sciences, Tehran, Iran.
Finetech in Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran.
BMC Ophthalmol. 2024 Aug 13;24(1):343. doi: 10.1186/s12886-024-03597-1.
Patients with von Hippel-Lindau (VHL) disease are at risk of developing tumors in the eye, brain, kidney, adrenal gland, and other organs based on their gene mutations. The VHL tumor suppressor gene contains pathogenic variants responsible for these events. This meta-analysis aims to investigate the genetic differences among the various types of VHL syndrome and their correlation with the location of mutations (exons and domains) in the VHL gene.
Papers eligible for publication until September 2023 were identified using the electronic databases of PubMed, Google Scholar, Scopus, and EMBASE. The Random Effect model was utilized to evaluate the genetic differences between type 1 and type 2 VHL syndromes.
The prevalence of missense mutations (MSs) was found to be 58.9% in type 1, while it was 88.1% in type 2. Interestingly, the probability of observing MSs in type 1 was 0.42 times lower compared to type 2. The mutation hotspots of the VHL gene were R167Q/W, Y98H, R238W, and S65L, respectively. Although type 2 had a high presentation of Y98H and R238W, it did not have a higher S65L than type 1. The analysis demonstrated a statistically significant higher prevalence of truncated mutations (PTMs) in type 1. Among type 1, large/complete deletions (L/C DELs) were found in 16.9% of cases, whereas in type 2 only 3.7%. This difference was statistically significant with a p-value < 0.001. Overall, the probability of identifying mutations in domain 2 compared to domain 1 was found to be 2.13 times higher in type 1 (p-value < 0.001). Furthermore, the probability of detecting exon 1 in comparison with observing exon 2 in type 1 was 2.11 times higher than type 2 and revealed a statistically significant result (p-value < 0.001). The detection of exon 2 was 2.18 times higher in type 1 (p-value < 0.001). In addition, the likelihood of discovering exon 2 compared with others was significantly lower in type 1 compared with type 2 VHL (OR = 0.63, p-value = 0.015).
We have revealed a comprehensive genetic difference between types 1 and 2 of VHL syndrome. The significant differences in MS, PTMs, L/C DELs, and the location of the mutations between type 1 and type 2 VHL patients in the Asian, European, and American populations emphasize the genetic heterogeneity of the syndrome. These findings may pave the way for the diagnosis, treatment, and further investigation of the mechanisms behind this complex genetic disorder.
根据基因突变，患有 von Hippel-Lindau（VHL）病的患者有在眼、脑、肾、肾上腺和其他器官中形成肿瘤的风险。VHL 肿瘤抑制基因包含导致这些事件的致病变体。本荟萃分析旨在研究各种类型的 VHL 综合征之间的遗传差异及其与 VHL 基因突变（外显子和域）位置的相关性。
使用 PubMed、Google Scholar、Scopus 和 EMBASE 的电子数据库，确定截至 2023 年 9 月的已发表论文。使用随机效应模型评估 1 型和 2 型 VHL 综合征之间的遗传差异。
1 型中发现错义突变（MSs）的患病率为 58.9%，而 2 型中为 88.1%。有趣的是，1 型中观察到 MSs 的概率比 2 型低 0.42 倍。VHL 基因突变的热点分别为 R167Q/W、Y98H、R238W 和 S65L。尽管 2 型的 Y98H 和 R238W 发生率较高，但 S65L 的发生率并不高于 1 型。分析表明 1 型中截短突变（PTMs）的患病率具有统计学意义。在 1 型中，大/完全缺失（L/C DELs）的发生率为 16.9%，而在 2 型中仅为 3.7%。这一差异具有统计学意义，p 值<0.001。总体而言，1 型中鉴定域 2 突变的概率比鉴定域 1 突变的概率高 2.13 倍（p 值<0.001）。此外，与 2 型相比，1 型中观察到外显子 1 的概率比观察到外显子 2 的概率高 2.11 倍，这是一个具有统计学意义的结果（p 值<0.001）。1 型中外显子 2 的检测率高 2.18 倍（p 值<0.001）。此外，与 2 型相比，1 型中外显子 2 的检出率明显较低（OR=0.63，p 值=0.015）。
我们揭示了 VHL 综合征 1 型和 2 型之间的全面遗传差异。1 型和 2 型 VHL 患者在亚洲、欧洲和美洲人群中 MS、PTMs、L/C DELs 和突变位置的显著差异强调了该综合征的遗传异质性。这些发现可能为这种复杂遗传疾病的诊断、治疗和进一步机制研究铺平道路。
