Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
Department of Transcriptional Regulation, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
Folia Biol (Praha). 2020;66(4):123-132. doi: 10.14712/fb2020066040123.
The aim of this study was to report PAX6 disease-causing variants in six Czech families, to describe the associated phenotypes, and to perform functional assessment of the splice site variants. Detailed ophthalmic examination was performed. The PAX6 coding region was directly sequenced in three probands. Two probands were analysed by exome sequencing and one by genome sequencing. The effect of two variants on pre-mRNA splicing was evaluated using an exon trapping assay. Six different heterozygous PAX6 variants were identified, with c.111_120del and c.1183+1G˃T being novel. Both c.1183+1G˃T and c.1032+1G>A were proved to cause aberrant splicing with exon skipping and subsequent frameshift. The phenotypic features were variable between and within families. One individual, aged 31 years, presented with mild unilateral ptosis accompanied by aniridia in the right eye, partial aniridia in the left eye, and bilateral congenital cataracts, without marked foveal hypoplasia. Bilateral microcornea, partial aniridia, congenital cataracts, and a large posterior segment coloboma were found in another proband, aged 32 years. One child, aged 8 years, had bilateral high myopia, optic nerve colobomas, anterior polar cataracts, but no iris defects. Another individual, aged 46 years, had bilateral congenital ptosis, iris hypoplasia, keratopathy with marked fibrovascular pannus, anterior polar cataract, and foveal hypoplasia combined with impaired glucose tolerance. However, his daughter, aged 11 years, showed classical features of aniridia. Our study extends the genetic spectrum of PAX6 disease-causing variants and confirms that the associated phenotypic features may be very broad and different to the 'classical' aniridia.
本研究旨在报告 6 个捷克家族中的 PAX6 致病变异，描述相关表型，并对剪接位点变异进行功能评估。进行了详细的眼科检查。在 3 个先证者中直接对 PAX6 编码区进行测序。对 2 个先证者进行外显子组测序，对 1 个先证者进行基因组测序。使用外显子捕获试验评估两种变体对前体 mRNA 剪接的影响。确定了六种不同的杂合 PAX6 变体，其中 c.111_120del 和 c.1183+1G>T 是新发现的。c.1183+1G>T 和 c.1032+1G>A 均被证明导致异常剪接，导致外显子跳过和随后的移码。表型特征在家族之间和家族内均存在差异。一位 31 岁的个体表现为右侧轻度单侧上睑下垂伴右眼虹膜缺失、左眼部分虹膜缺失和双侧先天性白内障，无明显的黄斑发育不良。另一位 32 岁的先证者发现双侧小角膜、部分虹膜缺失、先天性白内障和大后部节段性视杯缺损。一位 8 岁的儿童患有双侧高度近视、视神经视杯缺损、前极性白内障，但无虹膜缺损。另一位 46 岁的个体患有双侧先天性上睑下垂、虹膜发育不良、角膜病变伴明显纤维血管息肉、前极性白内障和黄斑发育不良合并葡萄糖耐量受损。然而，他 11 岁的女儿表现出典型的虹膜缺失特征。我们的研究扩展了 PAX6 致病变异的遗传谱，并证实相关表型特征可能非常广泛，与“经典”虹膜缺失不同。
