title: Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1.
abstract: Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
authors.affiliation: Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Carolina J
authors.initials: CJ
authors.lastname: Jorgez
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington, United States of America.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wilken
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hima V
authors.initials: HV
authors.lastname: Vangapandu
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dung
authors.initials: D
authors.lastname: Pham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Bandholz
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: David D
authors.initials: DD
authors.lastname: Weaver
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burton
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Deepti
authors.initials: D
authors.lastname: Babu
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: John S
authors.initials: JS
authors.lastname: Bamforth
authors.affiliation: Madigan Army Medical Center, Department of Pediatrics, Tacoma, Washington, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wilks
authors.affiliation: Department of Children's Endocrinology, St. Luke's Children's Specialty Center, Boise, Idaho, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flynn
authors.affiliation: Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Roeder
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sau W
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005835:Genitalia / Q000002:abnormalities; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D051857:Otx Transcription Factors / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D001743:Urinary Bladder / Q000002:abnormalities; D014564:Urogenital Abnormalities / Q000235:genetics*
chemical_list: C497655:OTX1 protein, human; D051857:Otx Transcription Factors