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Abstract：
Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.
摘要：
遗传性和发展性眼病种类繁多，由于它们的高等位基因和基因座异质性，确定它们的遗传原因具有挑战性。新的分子方法，如全外显子组测序（WES），已被证明是解决这些情况的强大分子工具。本研究使用WES鉴定了十例无关的墨西哥儿科患者的遗传病因，这些患者患有复杂的眼部异常和其他病因不明的全身性改变。WES方法使我们能够在GZF1、NFIX、TRRAP,与Larsen相关的FGFR2和PAX2基因，马兰,有或没有畸形相和自闭症的发育迟缓，LADD1和乳头状肾综合征。位于GZF1和NFIX中的突变被归类为致病性，TRRAP和FGFR2中的那些被分类为可能的致病性变异，PAX2中的那些被归类为未知意义的变异。两个错义FGFR2p的蛋白质建模。（Arg210Gln）和PAX2p。（Met3Thr）变体表明，这些变化可以诱导蛋白质重要功能区域的潜在结构改变。值得注意的是,五种变体中有四种以前没有报道过，除了TRRAP基因。因此,WES使40％的报告病例能够识别遗传原因。本文报道的所有综合征都非常罕见，表型可能与其他遗传实体重叠。
