Genotype–phenotype correlation of PAX6 gene mutations in aniridia

Abstract

The objective of this study was to investigate the genotype–phenotype correlation of the PAX6 gene in aniridia. We clinically examined 5 families and 16 sporadic patients with aniridia. We performed chromosomal analysis and PCR analysis of the PAX6 gene using patient genomic DNA. Chromosomal analysis demonstrated deletions at 11p13 in one allele in four sporadic patients. Seven nonsense mutations, two frameshifts (two insertions), four splice junction errors and two missense mutations were found, and all were heterozygous. The iris phenotype ranged from total to normal in each patient, and the characteristic phenotypes, including cataract, glaucoma or optic nerve hypoplasia, varied widely even among members of the same family. Foveal hypoplasia was detected in all patients except for one. No obvious genotype–phenotype correlation was identified; however, the aniridia phenotype between the two eyes in each patient was quite similar in all patients. Because PAX6 regulates numerous downstream genes and its expression is regulated by several factors during eye development, the aniridia phenotype may be complex even in family members. However, because PAX6 regulation, resulting from both paternal and maternal alleles associated with PAX6, is considered to be roughly similar in both eyes of each patient, the aniridia phenotype may be similar in both eyes of each patient.

Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay

“…The issue of the diverse phenotypic consequences of the different functional types of PAX6 variants has been discussed for a long time, but no statistically significant correlations have been detected [16]. One reason for that might be the incorrect classification of nucleotide variants into functional categories.…”

Panel‐based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns

“…Moreover, the complex gene expression networks in which transcription factors such as PAX6 and OTX2 participate, with several downstream targets, coactivators and corepressors regulated by both parental alleles, may result in phenotypic variation, even in cases with the same pathogenic variant (Yokoi et al. ). Secondly, epigenetic events or stochastic/environmental factors may also modify the final gene expression of these candidates, and thus the phenotypic outcome (Dipple and McCabe ; Ragge et al.…”

“…Firstly, studies in Otx2 +/À mice support the idea that the clinical variability is dependent on the genetic background (Hever et al 2006), suggesting that modifier genes or particular polymorphisms (in cis or trans) may enhance or suppress the phenotype by controlling the gene transcription levels. Moreover, the complex gene expression networks in which transcription factors such as PAX6 and OTX2 participate, with several downstream targets, coactivators and corepressors regulated by both parental alleles, may result in phenotypic variation, even in cases with the same pathogenic variant (Yokoi et al 2016). Secondly, epigenetic events or stochastic/environmental factors may also modify the final gene expression of these candidates, and thus the phenotypic outcome (Dipple and McCabe 2000;Ragge et al 2005a).…”

Congenital Aniridia with Ectopia Lentis

“…Larger deletions affecting the adjacent WT1 (Wilm's tumour) genes are the underlying cause of the WAGR syndrome [1,2]. Gene expression associated with PAX6 is regulated by both paternal and maternal alleles may result in phenotypic variation even in cases with the same PAX6 genotype [4]. Because there is considerable phenotypic variability, the clinician must perform a careful slit-lamp examination on other family members [4].…”