title: High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome.
abstract: Small submicroscopic genomic deletions and duplications constitute up to 15% of all mutations underlying human monogenic diseases. In this study, we used newly designed high-resolution oligonucleotide microarrays with a median distance between the probes of 776 bp (average probe interval 2,271 bp) to detect gene deletions in nevoid basal cell carcinoma syndrome (NBCCS) patients. NBCCS, also called Gorlin syndrome, is characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the human patched-1 (PTCH1) gene. Two out of three deletions could not be detected by a conventional chromosomal analysis. A submicroscopic deletion as small as 165 kb was detected affecting only PTCH1, whereas the other two deletions were much larger (5 and 11 Mb). We demonstrated not only the exact number of genes involved in the deletion but also rapidly determined the junction sequences after pinpointing the breakpoint regions in all individuals analyzed. This report of an array-based determination of junction sequences of long deletions circumvented a labor-intensive analysis such as Southern blotting or FISH. Alu-mediated recombination in one case and non-homologous end joining in the other two were probably implicated in the generation of deletions. This method will contribute to the understanding of molecular pathogenesis of gene deletions as well as rapid genetic testing.
authors: Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan.
authors: Katsunori
authors: K
authors: Fujii
authors: Shumpei
authors: S
authors: Ishikawa
authors: Hideki
authors: H
authors: Uchikawa
authors: Daisuke
authors: D
authors: Komura
authors: Michael H
authors: MH
authors: Shapero
authors: Fan
authors: F
authors: Shen
authors: Jing
authors: J
authors: Hung
authors: Hiroshi
authors: H
authors: Arai
authors: Yoko
authors: Y
authors: Tanaka
authors: Kimio
authors: K
authors: Sasaki
authors: Yoichi
authors: Y
authors: Kohno
authors: Masao
authors: M
authors: Yamada
authors: Keith W
authors: KW
authors: Jones
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Toshiyuki
authors: T
authors: Miyashita
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
chemical_list: D004273:DNA, Neoplasm; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface
references: Am J Hum Genet. 1996 Aug;59(2):417-22
references: 8755929
references: Cell. 1996 Jun 14;85(6):841-51
references: 8681379
references: Nat Rev Genet. 2006 Feb;7(2):85-97
references: 16418744
references: Eur J Pediatr. 2003 Feb;162(2):100-3
references: 12548386
references: Nat Genet. 2005 Jun;37 Suppl:S11-7
references: 15920524
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11237-42
references: 14500916
references: Genome Res. 2006 Dec;16(12):1575-84
references: 17122084
references: Nat Genet. 2006 Sep;38(9):974-6
references: 16941003
references: Science. 1996 Jun 14;272(5268):1668-71
references: 8658145
references: Genome Res. 2006 Aug;16(8):949-61
references: 16809666
references: No To Hattatsu. 2000 Jan;32(1):49-55
references: 10655752
references: Hum Mol Genet. 2005 Nov 15;14 (22):3379-88
references: 16203740
references: Hum Mutat. 2006 Mar;27(3):215-9
references: 16419085
references: Nat Genet. 2006 Jan;38(1):24-6
references: 16369530
references: Nucleic Acids Res. 2002 Jun 15;30(12 ):e57
references: 12060695
references: Hum Mol Genet. 2007 Mar 1;16(5):567-72
references: 17360722
references: Biochem Biophys Res Commun. 2005 Aug 12;333(4):1309-14
references: 15982637
references: Nature. 2006 Nov 23;444(7118):444-54
references: 17122850
references: Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4534-9
references: 16537408
references: Am J Med Genet A. 2003 Nov 15;123A(1):5-28
references: 14556242
references: Hum Mutat. 2005 Sep;26(3):283
references: 16088933
references: Am J Hum Genet. 1997 Jan;60(1):21-6
references: 8981943
references: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R215-23
references: 16244320
references: Genomics. 2005 Apr;85(4):462-71
references: 15780749
references: Hum Mutat. 2003 Apr;21(4):451-2
references: 12655573
references: Am J Med Genet. 1997 Mar 31;69(3):299-308
references: 9096761
references: Genome Res. 2004 Feb;14(2):287-95
references: 14762065
references: Nat Genet. 2006 Sep;38(9):999-1001
references: 16906164
references: Am J Med Genet A. 2005 Jan 30;132A(3):324-8
references: 15690381
references: Am J Med Genet A. 2004 Jan 15;124A(2):179-91
references: 14699618
references: Genome Res. 2003 Oct;13(10):2291-305
references: 12975311
references: Nat Rev Genet. 2002 May;3(5):370-9
references: 11988762
references: Clin Exp Dermatol. 2004 Sep;29(5):542-4
references: 15347344