Frequent Chromosome Aberrations Revealed by Molecular Cytogenetic Studies in Patients with Aniridia

Abstract

Seventy-seven patients with aniridia, referred for cytogenetic analysis predominantly to assess Wilms tumor risk, were studied by fluorescence in situ hybridization (FISH), through use of a panel of cosmids encompassing the aniridia-associated PAX6 gene, the Wilms tumor predisposition gene WT1, and flanking markers, in distal chromosome 11p13. Thirty patients were found to be chromosomally abnormal. Cytogenetically visible interstitial deletions involving 11p13 were found in 13 patients, 11 of which included WT1. A further 13 patients had cryptic deletions detectable only by FISH, 3 of which included WT1. Six of these, with deletions <500 kb, share a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4. Two of these six patients were mosaic for the deletion. The remaining four had chromosomal rearrangements: an unbalanced translocation, t(11;13), with a deletion including the WAGR (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) region, and three balanced rearrangements with what appear to be position effect breakpoints 3' of PAX6: (a) a t(7;11) with the 11p13 breakpoint approximately 30 kb downstream of PAX6, (b) a dir ins(12;11) with a breakpoint >50 kb from PAX6, and (c) an inv(11)(p13q13) with a breakpoint >75 kb downstream of PAX6. The proportion and spectrum of chromosome anomalies in familial (4/14, or 28.5%) and sporadic (26/63, or 41%) cases are not significantly different. An unexpectedly high frequency of chromosomal rearrangements is associated with both sporadic and familial aniridia in this cohort.

Gain of chromosome 8q is a frequent finding in pleuropulmonary blastoma

“…WT1 and PAX6 are involved in the pathogenesis of Wilms' tumors and the WAGR (Wilms' tumor, aniridia, genito-urinary abnormalities, mental retardation) syndrome. 33,34 In addition, 11p15.5, a chromosomal region known to harbor several imprinted genes, as well as genes also involved in pediatric tumorigenesis, is deleted in two patients. More specifically, several genes in this region have been implicated in the Beckwith-Wiedemann syndrome (BWS), such as CDKN1C and WT2.…”

Aniridia

“…Classical WAGR syndrome (MIM 194072) includes Wilms tumour with Aniridia, genitourinary abnormalities and mental Retardation, but the phenotype is highly variable. 3,4,19,20 Aniridia is the most consistent symptom. 3 The term 'WAGR syndrome' is generally used even if a patient does not exhibit all four classical features.…”

“…39 Chromosomal rearrangements in isolated aniridia and WAGR syndrome Isolated aniridia can also be caused by chromosomal deletions affecting all or part of the PAX6 region, or translocations and inversions that disrupt the transcription unit or control elements. 4,19,25,30 PAX6 is associated with a downstream cluster of highly conserved transcriptional regulatory elements, located in introns of the adjacent ELP4 gene. 26,40 If these elements are removed by a deletion or separated from the PAX6 transcription unit by an inversion or translocation break point, the typical outcome is classical aniridia.…”

“…Some molecular service labs still offer fluorescence in situ hybridisation (FISH) to identify rearrangements that might disrupt PAX6 function without copy number change. 19,25 In the future, however, whole-genome sequencing with paired-end sequencing will probably supersede FISH for identifying balanced rearrangements. 51,52 Targeted local deletion analysis is also possible using multiplex ligationdependent probe amplification (MLPA).…”

Cytogenetics and gene discovery in psychiatric disorders

“…In a recent study of aniridia, 30 of 77 patients studied were found to have a variety of chromosomal abnormalities including deletions and translocations around the Wilms tumour locus on 11p. 12 In addition to the germline chromosome rearrangements described above, somatic rearrangements in tumours and leukaemias have aided the identification of many new oncogenes and tumour suppressors. 13 Although a full description is outside the remit of this review, several models have been put forward to explain the mechanistic basis of translocation events.…”