title: Familial 46,XY sex reversal without campomelic dysplasia caused by a deletion upstream of the SOX9 gene.
abstract: BACKGROUND
  46,XY sex reversal is a rare disorder and familial cases are even more rare. The purpose of the present study was to determine the molecular basis for a family with three affected siblings who had 46,XY sex reversal.
  
  
  METHODS
  DNA was extracted from three females with 46,XY sex reversal, two normal sisters, and both unaffected parents. All protein coding exons of the SRY and NR5A1 genes were subjected to PCR-based DNA sequencing. In addition, array comparative genomic hybridization was performed on DNA from all seven family members. A deletion was confirmed using quantitative polymerase chain reaction. Expression of SOX9 gene was quantified using reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  A 349kb heterozygous deletion located 353kb upstream of the SOX9 gene on the long arm of chromosome 17 was discovered in the father and three affected siblings, but not in the mother. The expression of SOX9 was significantly decreased in the affected siblings. Two of three affected sisters had gonadoblastomas.
  
  
  CONCLUSIONS
  This is the first report of 46,XY sex reversal in three siblings who have a paternally inherited deletion upstream of SOX9 associated with reduced SOX9 mRNA expression.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of OB/GYN, University of Rochester Medical Center, Rochester, NY 14642, United States. Electronic address: bala_bhagavath@urmc.rochester.edu.
authors.forename: Bala
authors.initials: B
authors.lastname: Bhagavath
authors.affiliation: Section of Reproductive Endocrinology, Infertility and Genetics, Department of OB/GYN, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Layman
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.affiliation: Department of Pathology, Children's Hospital Boston, Boston, MA 02115, United States; Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA 02115, United States; Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Section of Reproductive Endocrinology, Infertility and Genetics, Department of OB/GYN, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Ha
authors.affiliation: Overlake Reproductive Health, 11232 NE 15th Street Suite 201, Bellevue, WA 98004, United States.
authors.forename: Khurram
authors.initials: K
authors.lastname: Rehman
authors.affiliation: Dept. of Biostatistics and Epidemiology, Georgia Regents University, 1120 15th Street, AE-1014, Augusta, GA 30912-4900, United States; Dept. of Oral Health and Diagnostic Sciences, Georgia Regents University, 1120 15th Street, AE-1014, Augusta, GA 30912-4900, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Looney
authors.affiliation: Section of Reproductive Endocrinology, Infertility and Genetics, Department of OB/GYN, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Paul G
authors.initials: PG
authors.lastname: McDonough
authors.affiliation: Section of Reproductive Endocrinology, Infertility and Genetics, Department of OB/GYN, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of OB/GYN, University of Texas Southwestern Medical Center, Dallas, TX 75235, United States.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Carr
mesh_terms: D055036:Campomelic Dysplasia / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006061:Gonadal Dysgenesis, 46,XY / Q000150:complications / Q000235:genetics*; D018238:Gonadoblastoma / Q000209:etiology; D006801:Humans; D016133:Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics*; D055815:Young Adult
chemical_list: D055758:SOX9 Transcription Factor
keywords: Gonadal dysgenesis; NR5A1; SOX9; SRY; XY sex reversal