Abstract
BackgroundSegmental duplicons (SDs) predispose to an increased frequency of chromosomal rearrangements. These rearrangements can cause a diverse range of phenotypes due to haploinsufficiency, in cis positional effects or gene interruption. Genomic microarray analysis has revealed gene dosage changes adjacent to duplicons, but the high degree of similarity between duplicon sequences has confounded unequivocal assignment of chromosome breakpoints within these intervals. In this study, we localize rearrangements within duplicon-enriched regions of Angelman/Prader-Willi (AS/PWS) syndrome chromosomal deletions with fluorescence in situ hybridization (FISH).ResultsBreakage intervals in AS deletions were localized recursively with short, coordinate-defined, single copy (SC) and low copy (LC) genomic FISH probes. These probes were initially coincident with duplicons and regions of previously reported breakage in AS/PWS. Subsequently, probes developed from adjacent genomic intervals more precisely delineated deletion breakage intervals involving genes, pseudogenes and duplicons in 15q11.2q13. The observed variability in the deletion boundaries within previously described Class I and Class II deletion AS samples is related to the local genomic architecture in this chromosomal region.ConclusionsChromosome 15 abnormalities associated with SDs were precisely delineated at a resolution equivalent to genomic Southern analysis. This context-dependent approach can define the boundaries of chromosome rearrangements for other genomic disorders associated with SDs.
Highlights
The human genome contains numerous regions that exhibit rare structural chromosome rearrangements due to segmental duplicons (SDs) that predispose to recurrent genomic disorders [1,2]
low copy (LC) intervals selected for probe development were based on: 1) their location in or adjacent to a region of frequent documented breakage; 2) up to 3 chromosome 15q11.2q13 targets detected by the LC probe; and 3) genomic separation of ≥ 5 Mb for at least 2 of 3 LC probe targets with chromosome 15q11.2q13
LC probe targets separated by less than 5 Mb could not be unequivocally discriminated by fluorescence in situ hybridization (FISH) as distinct loci on metaphase chromosomes
Summary
The human genome contains numerous regions that exhibit rare structural chromosome rearrangements due to segmental duplicons (SDs) that predispose to recurrent genomic disorders [1,2]. There are at least 20 distinct genomic sites in the human genome flanked by duplicons implicated in recurrent pathogenic rearrangements [3]. Among these are deletions of chromosome 15q11.2q13 in Angelman (AS [MIM 105830]) and Prader-Willi syndromes (PWS [MIM 176270]). Segmental duplicons (SDs) predispose to an increased frequency of chromosomal rearrangements These rearrangements can cause a diverse range of phenotypes due to haploinsufficiency, in cis positional effects or gene interruption. We localize rearrangements within duplicon-enriched regions of Angelman/Prader-Willi (AS/PWS) syndrome chromosomal deletions with fluorescence in situ hybridization (FISH)
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