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: 2.16). 03/2008; 146A(6):730-9. DOI: 10.1002/ajmg.a.32216
Source: PubMed


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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    ABSTRACT: FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2012; 158A(10):2430-8. DOI:10.1002/ajmg.a.35548 · 2.16 Impact Factor
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    • "The deletion sizes varied from 3.0 to 30 Mb with few common breakpoints and no smallest common region of deletion. Breakpoint clustering generally suggests an underlying susceptibility to rearrangements in the genomic architecture, such as segmental duplications, low-copy repeats (LCRs), and copy number variations (CNVs), all subject to nonallelic homologous recombination (NAHR) [Lindsey et al., 2006; Sharp et al., 2006; Conrad and Hurles, 2007; DeScipio et al., 2008] "
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    ABSTRACT: We report on two patients with overlapping small interstitial deletions involving regions 14q12 to 14q13.1. Both children had severe developmental delay, failure to thrive, microcephaly, and distinctive facial features, including abnormal spacing of the eyes, epicanthal folds, sloping forehead, low-set ears, rounded eyebrows with triangular media aspect and outer tapering, depressed and broad nasal bridge, small mouth, a long philtrum, and a prominent Cupid's bow. Brain MRI of both children showed partial agenesis of the corpus callosum. Our first patient had bilateral hypoplastic optic nerves causing blindness, mild hearing impairment, sinus arrhythmia, abnormal temperature regulation, frequent apneic episodes, myoclonic jerks, and opisthotonus. Our second patient had a seizure disorder confirmed by EEG, sleep apnea, chronic interstitial lung disease, and several episodes of pneumonia and gastroenteritis. Cytogenetic analysis showed a normal karyotype in Patient 1 and a unique apparently balanced three-way translocation in Patient 2 involving chromosomes 4, 14, and 11. High resolution SNP Oligonucleotide Microarray Analysis (SOMA) revealed a deletion in the proximal region of chromosome 14q overlapping with the deletion of our first patient, and no copy number changes in chromosomes 4 and 11. Here, we review and compare published cases with a deletion involving the 14q12-22.1 chromosomal region in an effort to correlate phenotype and genotype. We also examine the underlying genomic architecture to identify the possible mechanism of the chromosomal abnormality. Our review found a patient with a mirror duplication of our first patient's deletion, confirming the existence of an underlying genomic structural instability in the region. © 2011 Wiley-Liss, Inc.
    American Journal of Medical Genetics Part A 08/2011; 155A(8):1884-96. DOI:10.1002/ajmg.a.34090 · 2.16 Impact Factor
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    ABSTRACT: Submicroscopic deletion of the 6p25 subtelomere has recently been recognized as a clinically identifiable syndrome. To date, more than 30 cases have been described with variable cytogenetically visible 6p deletions. Terminal 6p deletions result in a clinically distinguishable phenotype. The focus of this review is the phenotype associated with isolated terminal deletions of 6p25, and specifically isolated submiscroscopic subtelomere deletions. A distinct phenotype has emerged consisting of developmental delay/mental retardation, language impairment, hearing loss, and ophthalmologic, cardiac, and craniofacial abnormalities. These features demonstrate considerable clinical overlap with the Ritscher-Schinzel (or cranio-cerebello-cardiac (3C)) syndrome (OMIM #220210). Isolated submiscroscopic 6p25 subtelomere terminal deletion has been reported in 11 individuals, two of whom are siblings. Cytogentic and molecular mapping of the 6p25 deletion boundary has been reported in 8 of these 10 unrelated individuals with isolated submiscroscopic subtelomere deletion. This analysis has revealed substantial phenotypic overlap between individuals with submicroscopic terminal 6p deletions and those with large, cytogenetically visible deletions of the region suggesting that the critical genes contributing to the main clinical and developmental features lie in the terminal region of 6p25.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 11/2007; 145C(4):377-82. DOI:10.1002/ajmg.c.30156 · 3.91 Impact Factor
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