title: A complex 6p25 rearrangement in a child with multiple epiphyseal dysplasia.
abstract: Genomic rearrangements are increasingly recognized as important contributors to human disease. Here we report on an 11½-year-old child with myopia, Duane retraction syndrome, bilateral mixed hearing loss, skeletal anomalies including multiple epiphyseal dysplasia, and global developmental delay, and a complex 6p25 genomic rearrangement. We have employed oligonucleotide-based comparative genomic hybridization arrays (aCGH) of different resolutions (44 and 244K) as well as a 1 M single nucleotide polymorphism (SNP) array to analyze this complex rearrangement. Our analyses reveal a complex rearrangement involving a ∼2.21 Mb interstitial deletion, a ∼240 kb terminal deletion, and a 70-80 kb region in between these two deletions that shows maintenance of genomic copy number. The interstitial deletion contains eight known genes, including three Forkhead box containing (FOX) transcription factors (FOXQ1, FOXF2, and FOXC1). The region maintaining genomic copy number partly overlaps the dual specificity protein phosphatase 22 (DUSP22) gene. Array analyses suggest a homozygous loss of genomic material at the 5' end of DUSP22, which was corroborated using TaqMan® copy number analysis. It is possible that this homozygous genomic loss may render both copies of DUSP22 or its products non-functional. Our analysis suggests a rearrangement mechanism distinct from a previously reported replication-based error-prone mechanism without template switching for a specific 6p25 rearrangement with a 1.22 Mb interstitial deletion. Our study demonstrates the utility and limitations of using oligonucleotide-based aCGH and SNP array technologies of increasing resolutions in order to identify complex DNA rearrangements and gene disruptions.
authors.affiliation: Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, USA. sarahbed@med.umich.edu
authors.forename: Jirair K
authors.initials: JK
authors.lastname: Bedoyan
authors.forename: Marci M
authors.initials: MM
authors.lastname: Lesperance
authors.forename: Todd
authors.initials: T
authors.lastname: Ackley
authors.forename: Ramaswamy K
authors.initials: RK
authors.lastname: Iyer
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Misra
mesh_terms: D001483:Base Sequence; D002648:Child; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D004370:Duane Retraction Syndrome / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010009:Osteochondrodysplasias / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; D054639:Mitogen-Activated Protein Kinase Phosphatases; C442824:DUSP22 protein, human; D054637:Dual-Specificity Phosphatases