Copyright © 2005 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 76, Issue 4, 652-662, 1 April 2005
doi:10.1086/429252
Report
Position Effects Due to Chromosome Breakpoints that Map ∼900 Kb Upstream and ∼1.3 Mb Downstream of SOX9 in Two Patients with Campomelic Dysplasia
Gopalrao V.N. Velagaleti1, 2, *, Gabriel A. Bien-Willner3, *, Jill K. Northup1, Lillian H. Lockhart2, Judy C. Hawkins2, Syed M. Jalal6, Marjorie Withers3, James R. Lupski3, 4, 5 and Pawel Stankiewicz3, 
, 
1 Department of Pathology, University of Texas Medical Branch, Galveston
2 Department of Pediatrics, University of Texas Medical Branch, Galveston
3 Department of Molecular and Human Genetics and
4 Department of Pediatrics, Baylor College of Medicine, Houston
5 Texas Children's Hospital, Houston
6 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Address for correspondence and reprints: Dr. Pawel Stankiewicz, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room T821, Houston, TX 77030* These authors contributed equally to this article.
Abstract
Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y–related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.
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