Analysis of genotype–phenotype correlations in PAX6-associated aniridia

Abstract

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher’s exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini–Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3′-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia

“…Hence, a limitation of this study is that the age of ARK onset was not accurately discernible, and it was not possible to apply an ARK grading in this investigation. Although our prevalence rate was 68.6% (118/172 eyes), in line with that previously reported (48-80%) (7,38,47,57), the true rates may be higher. A prospective study would facilitate the acquisition of more detailed information on the development and progression of ARK and its relationship to various surgical interventions.…”

“…Clinical features such as foveal hypoplasia was observed in three-quarters of patients, and nystagmus in 87.2%, corresponding with reported prevalence rates of 78%-93% and 58%-95%, respectively (3,7,39,47,50). Previously, the most severe grade of foveal hypoplasia (grade 3 or 4) was associated with PTCs, and milder grades (grade 1 and 2) associated with gene deletions (51).…”

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

“…A previously conducted in RCMG molecular genetic study revealed four patients with the typical clinical picture of congenital aniridia (Table 1) (Vasilyeva, Voskresenskaya, Kasmann‐Kellner, et al, 2017; Vasilyeva et al, 2020), in whom MLPA analysis did not identify large deletions affecting PAX6 and/or its cis ‐regulatory regions and Sanger sequencing of the coding regions and splice sites of PAX6 did not reveal potential causative variants. However, we found variants located within the 5ʹUTR in these patients: two novel variants, that have been classified as variants of uncertain clinical significance (c.‐122dupG (described for the first time), c.‐125dupG (Vasilyeva, Voskresenskaya, Kasmann‐Kellner, et al, 2017) and two variants that were previously reported in unrelated patients and therefore could be classified as likely pathogenic (c.‐128‐2delA (Axton et al, 1997; Plaisancie et al, 2018; Robinson et al, 2008; Vasilyeva, Voskresenskaya, Kasmann‐Kellner, et al, 2017), c.‐118_‐117del (Plaisancie et al, 2018; Vasilyeva et al, 2020)). Clinically these four patients showed almost complete (three patients) or partial aniridia (one patient), foveal hypoplasia (four patients), and nystagmus (three patients).…”

PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism

“…These variable phenotypes are likely due to the physicochemical differences of the resulting amino acid and its effect in the DNA-binding activity of the PD [19]. However, it has recently been noted that some missense changes are likely to affect splicing mechanisms, which could in fact result in loss of function variants, perhaps explaining the cases presenting with iris phenotype [20]. Germline or postzygotic mosaicism has long been suspected to be a cause for apparent de novo cases with PAX6 variants [21,22], but only recently it was confirmed by analysis of different somatic tissues of suspected carriers [10].…”