Phenotype Variability in Czech Patients Carrying PAX6 Disease-Causing Variants

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• PAX6 gene mutations are a known cause of aniridia and other developmental eye disorders.
• The genetic and phenotypic spectrum of PAX6-related diseases requires further elucidation.

Purpose of the Study:

• To identify and characterize PAX6 disease-causing variants in six Czech families.
• To describe the associated ocular phenotypes.
• To functionally assess the impact of identified splice site variants on PAX6 gene expression.

Main Methods:

• Genetic analysis including direct sequencing, exome sequencing, and genome sequencing.
• Ophthalmic examinations to assess patient phenotypes.
• Exon trapping assays to evaluate the functional impact of splice site variants on pre-mRNA splicing.

Main Results:

• Six distinct heterozygous PAX6 variants were identified, including two novel variants (c.111_120del and c.1183+1G˃T).
• Two variants (c.1183+1G˃T and c.1032+1G>A) were confirmed to cause aberrant splicing, leading to exon skipping and frameshift.
• Phenotypic presentations were highly variable, ranging from classical aniridia to high myopia, colobomas, ptosis, and keratopathy, even within families.

Conclusions:

• The study expands the known spectrum of PAX6 variants associated with eye diseases.
• PAX6 variants can lead to a wide range of ocular phenotypes, often differing significantly from classical aniridia.
• Functional validation confirms the pathogenicity of identified splice site variants through disruption of splicing.