The genetic architecture of aniridia and Gillespie syndrome

Abstract

Absence of part or all of the iris, aniridia, is a feature of several genetically distinct conditions. This review focuses on iris development and then the clinical features and molecular genetics of these iris malformations. Classical aniridia, a panocular eye malformation including foveal hypoplasia, is the archetypal phenotype associated with heterozygous PAX6 loss-of-function mutations. Since this was identified in 1991, many genetic mechanisms of PAX6 inactivation have been elucidated, the commonest alleles being intragenic mutations causing premature stop codons, followed by those causing C-terminal extensions. Rarely, aniridia cases are associated with FOXC1, PITX2 and/or their regulatory regions. Aniridia can also occur as a component of many severe global eye malformations. Gillespie syndrome—a triad of partial aniridia, non-progressive cerebellar ataxia and intellectual disability—is phenotypically and genotypically distinct from classical aniridia. The causative gene has recently been identified as ITPR1 . The same characteristic Gillespie syndrome-like iris, with aplasia of the pupillary sphincter and a scalloped margin, is seen in ACTA2 -related multisystemic smooth muscle dysfunction syndrome. WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies and mental retardation/intellectual disability), is caused by contiguous deletion of PAX6 and WT1 on chromosome 11p. Deletions encompassing BDNF have been causally implicated in the obesity and intellectual disability associated with the condition. Lastly, we outline a genetic investigation strategy for aniridia in light of recent developments, suggesting an approach based principally on chromosomal array and gene panel testing. This strategy aims to test all known aniridia loci—including the rarer, life-limiting causes—whilst remaining simple and practical.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

“…39 For aniridia, genetic testing is particularly important as it allows early detection/exclusion of two molecular subtypes (accounting for~10% of aniridia cases) that are associated with life limiting complications: WAGR syndrome [MIM 194072] and ACTA2-related multisystemic smooth muscle dysfunction [MIM 613834]. 40 For albinism, it is known that syndromic forms of the disease (HPS and Chediak-Higashi syndrome [MIM 214500]) can be overlooked, especially in young children. Affected individuals may therefore remain undiagnosed until later in life unless genetic testing is performed; this is concerning as these patients require specific management to prevent life limiting complications.…”

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

“…Chromosomal rearrangements (deletions, duplications, translocations, or inversions) involving part or whole PAX6 gene or regulatory elements account for up to 10% of all aniridia cases. Some reports suggest that the PAX6 deletions are more frequent in sporadic as compared to familial aniridia patients, while others found no significant difference [84,[100][101][102]. Large deletions that encompass PAX6 and other neighbour genes, such as WT1, result in systemic disease, such as WAGR, caracterised by the presence of Wilms tumour, aniridia, genitourinary anomalies, and retardation characterize (described in Section 6.2).…”

“…It is estimated that 5% of aniridia patients remain without molecular diagnosis, pointing to more PAX6 regulatory regions, modifiers, or even novel genes to be discovered [102].…”

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…3a). The typical phenotype associated with heterozygous variants of this gene is aniridia (absence of the iris) with associated manifestations in other ocular structures, for example foveal hypoplasia, and corneal opacification (Hall et al 2018). Atypical presentations include Peters' anomaly, corectopia, isolated foveal hypoplasia, optic nerve malformations (hypoplasia and coloboma), cataract and nystagmus (usually related to reduced visual function) (Hever et al 2006;Tzoulaki et al 2005).…”