Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.,Clinical Genetics

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Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-08-15 , DOI: 10.1111/cge.13830
Farrah Islam ₁ , Stephanie Htun ₂ , Li-Wen Lai ₃ , Max Krall ₂ , Menitha Poranki ₂ , Pierre-Marie Martin ₄ , Nara Sobreira ₅ , Elizabeth S Wohler ₅ , Jingwei Yu ₆ , Anthony T Moore ₇ , Anne M Slavotinek ₂

Affiliation

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.

中文翻译：

来自近亲人群的小眼、无眼和缺损 (MAC) 患者的外显子组测序。

新一代测序策略在小眼畸形、无眼畸形和缺损 (MAC) 患者的小队列中实现了 21% 至 61% 的突变检测率，但尽管在识别新的致病基因方面取得了进展，但许多患者仍然没有进行基因诊断。我们研究了一组 19 名 MAC 患者，这些患者是从具有高血缘关系的人群中确定的。使用单核苷酸多态性 (SNP) 阵列和全外显子组测序 (WES)，我们在一名白内障患者以及 MAC 患者的TENM3中发现了一个致病性变异。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，并鉴定了来自 Wnt 信号通路的 MAC 候选基因的变异，包括LRP6、WNT2B和IQGAP1，但我们的研究结果并未证明因果关系。许多病例没有发现合理的变异，这表明我们目前对 MAC（一种高度异质性的眼部缺陷组）的发病机制的理解仍然不完整。

更新日期：2020-10-21

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