Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations

Abstract

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

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

“…Further analysis of segregation of this SNV in pedigree showed proband's grandfather carried the variant and had no signs of aniridia. The deletion affecting PTC/NMD premature termination codon formation followed by mRNA degradation through the nonsense mediated decay pathway the PAX6 distal 3′-cis-regulatory region was found in a proband [2].…”

“…A previously conducted molecular genetics study of a cohort of 110 patients from 84 unrelated Russian families with a clinical diagnosis of congenital aniridia revealed six single nucleotide variants out of canonical splicing site dinucleotides, which may affect splicing: five intronic (c.142−5T>G, c.142−14C>G, c.141+4A>G, c.1032+6T>G, c.682+4delA) and one missense variants (c.140A>G) [2]. Two more PAX6 sequence variants were newly identified later: one synonymous (c.174C>T) and one deep-intronic (c.142−64A>C) (unpublished data).…”

The Spectrum of PAX6 Mutations and Genotype-Phenotype Correlations in the Eye

“…PTCs in this region are expected to escape NMD and they would result in truncated proteins with a possible dominant negative effect and more severe phenotypes [81,82]. However, within the region that was predicted to escape NMD, i.e., the last 50 bp from exon 12 and exon 13, there are no nonsense mutations reported aside from c.1183G>T (p.Gly395*) in the last nucleotide of exon 12, but with predicted mRNA missplicing [83], and all frameshift changes are predicted to cause C-terminal extensions [78].…”

Extension of the mutation spectrum of PAX6 from three Chinese congenital aniridia families and identification of male gonadal mosaicism

“…It is well accepted that the frameshift mutation c.879_880delCA (p.S294Cfs*46) can cause congenital aniridia, which leaded to a truncated protein. In reviewing previous literatures, we found that there are two frameshift mutations reported pathogenic at the same genome coordinate, which are c.879delC (p.Ser294Valfs*71) and c.879dupC (p.T293fsX47) (Vasilyeva et al., ; Villarroel et al., ). According to the ACMG STANDARD AND GUIDELINES 2015 (Richards et al., ), the frameshift variants at c.879 of PAX6 are pathogenic and its pathogenicity evidence grade PVS1 is high.…”