Department of Ophthalmology, Al-Shifa Eye Trust Hospital, Rawalpindi, Pakistan.
Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
Clin Genet. 2020 Nov;98(5):499-506. doi: 10.1111/cge.13830. Epub 2020 Sep 3.
Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.
下一代测序策略在患有小眼症、无眼症和虹膜缺损（MAC）的小患者队列中检测到了 21%至 61%的突变率，但尽管在识别新的致病基因方面取得了进展，许多患者仍然没有遗传诊断。我们研究了一个由具有高近亲结婚率的人群中确定的 19 名 MAC 患者的队列。使用单核苷酸多态性（SNP）阵列和全外显子组测序（WES），我们在一名除了 MAC 之外还有白内障的患者中发现了 TENM3 中的一个致病性变异。我们还在以前与 MAC 相关的基因中检测到了未知意义的新变异，包括 KIF26B、MICU1 和 CDON，并在 Wnt 信号通路的 MAC 候选基因中鉴定到了变异，包括 LRP6、WNT2B 和 IQGAP1，但我们的发现并不能证明因果关系。许多病例都没有发现合理的变异，这表明我们目前对 MAC 的发病机制的理解仍然不完整，MAC 是一组高度异质性的眼部缺陷。
