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

Abstract

Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterised by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma and aniridia related keratopathy (ARK). Genotype-phenotype correlations have previously been described, however detailed longitudinal studies of aniridia are less commonly reported. We identified eighty-six patients from sixty-two unrelated families with molecularly confirmed heterozygous PAX6 variants from a United Kingdom (UK)-based single-centre ocular genetics service. They were categorised into mutation groups and retrospective review of baseline to most recent clinical characteristics (ocular and systemic) were recorded. One hundred and seventy-two eyes were evaluated, with a mean follow up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2%, and foveal hypoplasia in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6% and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention varied amongst mutation groups. Overall, the missense mutation sub-group had the mildest phenotype, and surgically naïve eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8%, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the United Kingdom, providing insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features.

Foveal Hypoplasia Grading in 95 Cases of Congenital Aniridia: Correlation to Phenotype and PAX6 Genotype

“…This retinal genotype-phenotype correlation is concordant with the predicted functional outcomes of deletions of these downstream regulatory regions of PAX6 which are expected to affect the level of PAX6 expression most probably in a lesser extent than mutations resulting in complete loss of PAX6 function. These results are according to those from smaller series previously reported, 2,5 with the exception of CTE variants that have been recently associated with less severe retinal phenotype in 2 of 3 patients. 2 This discrepancy may be explained by the small number of patients studied.…”

“…These results are according to those from smaller series previously reported, 2,5 with the exception of CTE variants that have been recently associated with less severe retinal phenotype in 2 of 3 patients. 2 This discrepancy may be explained by the small number of patients studied. Interestingly, variants altering the initiation codon of PAX6 led to variable retinal phenotype, that can be explained by the fact that they can lead either to complete failure of translation from the natural start site of PAX6 with no protein produced, or to translation starting at a downstream cryptic site producing a partially functional mutant PAX6 protein.…”

“…9,10 Grades 2 or 3 of arrested foveal development were associated with PAX6 missense variants located in the paired domain or in the homeodomain. Contrary, Kit V et al 2 have reported that all eyes of patients with missense mutations (n=9 /29 eyes) showed milder grades of foveal hypoplasia. The severity of the retinal phenotype of such variants is likely to depend on their exact functional consequences, which can be difficult to establish without in vitro functional assays.…”

“…However, in other cases, the entire iris may be present and apparently intact or with only subtle changes, making the genetic testing necessary to establish the final diagnosis of aniridia. 2 Human PAX6 (MIM#607108) is the major gene responsible for autosomal dominant forms of congenital aniridia with more than 500 pathogenic variants reported to date. 3 A wide range of loss-of-function variants in PAX6 introducing premature termination codons (PTC), predicted to cause haploinsufficiency due to nonsense-mediated decay (NMD) of the mRNA, are the main genetic causes of congenital aniridia.…”

“…4 However, few studies have carefully evaluated foveal hypoplasia associated with PAX6 due to issues such as small sample sizes in case series or lack of PAX6 genotype confirmation. 2,5,6 Owing to high resolution imaging of the retina by SD-OCT, Thomas et al were pioneers to establish a valuable grading scheme for foveal hypoplasia and to show significant correlation between the grade of foveal hypoplasia and visual acuity in a series of patients with albinism, achromatopsia, and 10 PAX6-related aniridia patients. 7 Recently, another study on 34 participants with confirmed PAX6 genotypes, showed that mutations in non-coding PAX6 regions had thicker foveal outer retinal layers than those with mutations in coding regions.…”