Article

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

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.05). 03/2008; 146A(6):730-9. DOI: 10.1002/ajmg.a.32216
Source: PubMed

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.

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    • ") is a contiguous gene deletion syndrome characterized by various anomalies including ocular anterior segment dysgenesis reminiscent of Axenfeld– Rieger syndrome (ARS), hypertelorism, down-slanting palpebral fissures, flat nasal bridge, dental anomalies, congenital heart defects, Dandy–Walker malformation, hearing loss, and developmental delay. 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). "
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