Fine‐mapping subtelomeric deletions and duplications by comparative genomic hybridization in 42 individuals

Abstract

Human subtelomere regions contain numerous gene-rich segments and are susceptible to germline rearrangements. The availability of diagnostic test kits to detect subtelomeric rearrangements has resulted in the diagnosis of numerous abnormalities with clinical implications including congenital heart abnormalities and mental retardation. Several of these have been described as clinically recognizable syndromes (e.g., deletion of 1p, 3p, 5q, 6p, 9q, and 22q). Given this, fine-mapping of subtelomeric breakpoints is of increasing importance to the assessment of genotype-phenotype correlations in these recognized syndromes as well as to the identification of additional syndromes. We developed a BAC and cosmid-based DNA array (TEL array) with high-resolution coverage of 10 Mb-sized subtelomeric regions, and used it to analyze 42 samples from unrelated patients with subtelomeric rearrangements whose breakpoints were previously either unmapped or mapped at a lower resolution than that achievable with the TEL array. Six apparently recurrent subtelomeric breakpoint loci were localized to genomic regions containing segmental duplication, copy number variation, and sequence gaps. Small (1 Mb or less) candidate gene regions for clinical phenotypes in separate patients were identified for 3p, 6q, 9q, and 10p deletions as well as for a 19q duplication. In addition to fine-mapping nearly all of the expected breakpoints, several previously unidentified rearrangements were detected.

The 6p subtelomere deletion syndrome

“…TEL array provides complete ($1.5Â coverage) tiling path coverage for the terminal 5 Mb region of 6p25 [DeScipio et al, 2007]. The TEL array data revealed a conflict with our previously reported mapping data for Patient 8, revealing an $3.9 Mb deletion (defined by BAC RP11-590A14) rather than $3.0 Mb as we had previously reported [DeScipio et al, 2005].…”

“…The minimally deleted critical region in 6p subtelomere deletion syndrome, as defined by this individual, was therefore determined to be the terminal $1.3 Mb region of chromosome 6p [DeScipio et al, 2005]. We have subsequently reanalyzed the 6p-deleted region in Patient 8 by array CGH using a custom made BAC and cosmid based DNA array (TEL array) with high-resolution coverage of telomeric and subtelomeric regions [DeScipio et al, 2007].…”

“…The TEL array provides coverage of the most distal 10 Mb of each chromosome arm (excluding the satellite stalks of the acrocentric chromosomes 13, 14, 15, 21, and 22), and thus covers all of the subtelomeric regions likely to give rise to cryptic subtelomeric cytogenetic changes [DeScipio et al, 2007]. TEL array provides complete ($1.5Â coverage) tiling path coverage for the terminal 5 Mb region of 6p25 [DeScipio et al, 2007].…”

De novo balanced chromosome rearrangements in prenatal diagnosis

“…One possible explanation for the preferential involvement of certain chromosomes in structural anomalies could be researched in their genomic architecture. Indeed, segmental duplications, representing 4-5% of the human genome (Bailey et al, 2002;Zhang et al, 2005), have been found to be predisposing factors in chromosomal rearrangements leading to disease (Stankiewicz et al, 2002) and, more recently, recurrent subtelomeric BKPs have been localized to genomic regions containing low copy repeats (DeScipio et al, 2008). The extent of segmental duplications has been reported to vary from 1 to 14% among the 24 chromosomes, with an approximate average of 4% (Zhang et al, 2005).…”

Pre‐ and postnatal phenotype of 6p25 deletions involving the FOXC1 gene

“…The many patients described to date had terminal 6p25 deletions [Law et al, 1998;Nishimura et al, 1998;Gould et al, 2004;Le Caignec et al, 2005;Rosenberg et al, 2006;Martinez-Glez et al, 2007;DeScipio et al, 2008;Martinet et al, 2008], interstitial 6p25 deletions [van Swaay et al, 1988;Davies et al, 1999;Lehmann et al, 2002;Koolen et al, 2005;Chanda et al, 2008;D'Haene et al, 2011], or mixed 6p25 deletions [Bedoyan et al, 2011]. However, molecular characterization of the deletion was performed in only a minority of patients (using FISH and/or STS marker analysis in 26 cases and array-CGH or SNP chips in 18 cases).…”