A complex 6p25 rearrangement in a child with multiple epiphyseal dysplasia

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. © 2010 Wiley‐Liss, Inc.