Bala Bhagavath1, Lawrence C Layman2, Reinhard Ullmann3, Yiping Shen4, Kyungsoo Ha2, Khurram Rehman5, Stephen Looney6, Paul G McDonough2, Hyung-Goo Kim2, Bruce R Carr7. 1. 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. 2. Section of Reproductive Endocrinology, Infertility and Genetics, Department of OB/GYN, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, United States. 3. Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany. 4. 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. 5. Overlake Reproductive Health, 11232 NE 15th Street Suite 201, Bellevue, WA 98004, United States. 6. 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. 7. Division of Reproductive Endocrinology and Infertility, Department of OB/GYN, University of Texas Southwestern Medical Center, Dallas, TX 75235, United States.
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. CONCLUSION: 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.
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. CONCLUSION: 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.
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