title: SNP array mapping of chromosome 20p deletions: genotypes, phenotypes, and copy number variation.
abstract: The use of array technology to define chromosome deletions and duplications is bringing us closer to establishing a genotype/phenotype map of genomic copy number alterations. We studied 21 patients and five relatives with deletions of the short arm of chromosome 20 using the Illumina HumanHap550 SNP array to: 1) more accurately determine the deletion sizes; 2) identify and compare breakpoints; 3) establish genotype/phenotype correlations; and 4) investigate the use of the HumanHap550 platform for analysis of chromosome deletions. Deletions ranged from 95 kb to 14.62 Mb, and all of the breakpoints were unique. Eleven patients had deletions between 95 kb and 4 Mb and these individuals had normal development, with no anomalies outside of those associated with Alagille syndrome (AGS). The proximal and distal boundaries of these 11 deletions constitute a 5.4-Mb region, and we propose that haploinsufficiency for only 1 of the 12 genes in this region causes phenotypic abnormalities. This defines the JAG1-associated critical region, in which deletions do not confer findings other than those associated with AGS. The other 10 patients had deletions between 3.28 Mb and 14.62 Mb, which extended outside the critical region, and, notably, all of these patients had developmental delay. This group had other findings such as autism, scoliosis, and bifid uvula. We identified 47 additional polymorphic genome-wide copy number variants (>20 SNPs), with 0 to 5 variants called per patient. Deletions of the short arm of chromosome 20 are associated with relatively mild and limited clinical anomalies. The use of SNP arrays provides accurate high-resolution definition of genomic abnormalities.
authors.affiliation: Division of Gastroenterology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Binita M
authors.initials: BM
authors.lastname: Kamath
authors.forename: Brian D
authors.initials: BD
authors.lastname: Thiel
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.forename: Pedro S
authors.initials: PS
authors.lastname: Munoz
authors.forename: Joseph
authors.initials: J
authors.lastname: Glessner
authors.forename: Dinah
authors.initials: D
authors.lastname: Clark
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Warthen
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
authors.forename: Ercan
authors.initials: E
authors.lastname: Mihci
authors.forename: David A
authors.initials: DA
authors.lastname: Piccoli
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics; D002872:Chromosome Deletion; D002874:Chromosome Mapping / Q000379:methods*; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D007621:Karyotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D046228:Microarray Analysis / Q000379:methods*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins