Abstract
Chromosomal deletions at 11p13 are a frequent cause of congenital Aniridia, a rare pan-ocular genetic disease, and of WAGR syndrome, accounting up to 30% of cases. First-tier genetic testing for newborn with aniridia, to detect 11p13 rearrangements, includes Multiplex Ligation-dependent Probe Amplification (MLPA) and karyotyping. However, neither of these approaches allow obtaining a complete picture of the high complexity of chromosomal deletions and breakpoints in aniridia. Here, we report the development and validation of a customized targeted array-based comparative genomic hybridization, so called WAGR-array, for comprehensive high-resolution analysis of CNV in the WAGR locus. Our approach increased the detection rate in a Spanish cohort of 38 patients with aniridia, WAGR syndrome and other related ocular malformations, allowing to characterize four undiagnosed aniridia cases, and to confirm MLPA findings in four additional patients. For all patients, breakpoints were accurately established and a contiguous deletion syndrome, involving a large number of genes, was identified in three patients. Moreover, we identified novel microdeletions affecting 3' PAX6 regulatory regions in three families with isolated aniridia. This tool represents a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a more accurate CNVs detection, as well as a better delineation of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns and those without defects in PAX6 after diagnostic screening.
Highlights
Congenital aniridia [MIM#106210] is a rare genetic pan-ocular disease characterized by the complete or partial absence of the iris
Nineteen families had been diagnosed with isolated or syndromic aniridia, including: i) 13 patients without intragenic PAX6 mutations after Sanger sequencing; ii) four patients carrying a previously known 11p13 microdeletion detected by Multiplex Ligation-dependent Probe Amplification (MLPA), that were used as positive controls for validation purposes, and iii) two cases carrying a coding PAX6 mutation, that were used as negative control samples
Four samples from isolated aniridia or WAGR patients with known 11p13 deletions previously identified by MLPA (ANIRIDIA-020, ANIRIDIA-039, ANIRIDIA-064 and ANIRIDIA-067; Table 1) were used as positive controls; they ranged from a small deletion, affecting apparently only two exons of PAX6, to large rearrangements encompassing multiple genes
Summary
Congenital aniridia [MIM#106210] is a rare genetic pan-ocular disease characterized by the complete or partial absence of the iris. It can appear uni- or bilaterally, isolated or in association to other ocular and/or systemic anomalies. Up to 30% of patients with aniridia carry chromosomal rearrangements at 11p13, with a high degree of breakpoint complexity [5, 6], including whole-gene deletions, microdeletions affecting only 3 ́ regulatory enhancers [5, 7,8,9,10,11,12] or contiguous gene deletions of PAX6 and other neighboring genes, mainly WT1 which is associated to WAGR syndrome [1, 13]
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