Familial aniridia spectrum in four families of Czech origin with PAX6 mutations

• Published in: Acta ophthalmologica (Oxford, England) England), 2019-12, Vol.97 (S263), p.n/a
• Main Authors: Moravikova, Jana, Dudakova, Lubica, Kozmik, Zbynek, Skalicka, Pavlina, Liskova, Petra
• Format: Article
• Language: English
• Subjects: Aniridia; Anterior segment dysgenesis syndrome; Cataracts; Deoxyribonucleic acid; DNA; Etiology; Eye; Hypoplasia; Iris; mRNA; Mutation; Paternity; Paternity testing; Pax6 protein; Phenotypes; Saliva; Splicing
• ISSN: 1755-375X; 1755-3768
• DOI: 10.1111/j.1755-3768.2019.5365

Purpose To identify disease‐causing mutations in four families with aniridia spectrum of Czech origin, to describe the associated phenotypes and to perform functional assessment of mutations located in canonical splice sites. Methods After complex ophthalmic examination of all available family members, DNA extraction from blood or saliva samples was performed. All coding regions of PAX6 gene were Sanger sequenced. In two cases of mutations which could potentially affect splicing of pre‐mRNA functional reassessment was accomplished using Exontrap vector. In one family paternity testing using a standard set of markers was performed. Results In total 13 affected individuals were examined. Except for common finding in aniridia, one individual had partial aniridia in the right eye and iris hypoplasia in the left eye, had bilateral ptosis, keratopathy with marked fibrovascular pannus, anterior polar cataracts, foveal hypoplasia, hepatopathy and trombocytopenia of unclear etiology. His affected daughter showed classical aniridia with total absence of iris and foveal hypoplasia in both eyes. Another individual had mild unilateral ptosis and anterior and posterior subcapsular cataracts. Bilateral microcornea, partial aniridia, surgically removed congenital cataracts and large posterior segment coloboma were present in another patient. In four probands, four different PAX6 mutations were identified, one mutation was novel (c.1183+1G>T). Two of detected variants were proven to affect pre‐mRNA splicing by skipping of adjutant exon sequences from mature mRNA. Conclusion Loss of visual functions in anterior segment dysgenesis disorders is often very severe, therefore establishing molecular diagnosis highly impacts patient management, enabling prenatal and preimplantation diagnostics. Our study enlarges the spectrum of known PAX6 mutations and confirms that anirida spectrum may also encompass combination of congenital ptosis, severe keratopathy and anterior polar cataracts. Vector Exontrap has been shown as an effective system for the evaluation of variants in canonical splicing sites. Funding Supported by SVV 260367/2017 and GAUK 82318‐2018.