Genetics of Sex Determination
Harry Ostrer, M.D., Carole Oddoux, Ph.D., NYU School of Medicine
In humans and other mammals, sex determination generally proceeds in the direction of female development unless genes involved in testis determination are activated. The SRY gene (for "sex-determining region Y") is believed to be the switch that initiates the testis development.
Deregulation of the sex pathway leads to abnormal sex differentiation and, in some cases, to complete sex reversal (genetic sex of one type, chromosomal sex of the opposite type).
The identification and cloning of sex-determining genes depends on the investigation of patients with sex reversal syndromes, some with chromosomal rearrangements.
In addition to SRY, autosomal and X-linked loci have also been linked with failure to develop a testis and thus, sex reversal (table).
| Genes Involved in Male Sexual Development | |||
|---|---|---|---|
| Gene | Chromosomal Region | Associated syndrome when mutated (m) or duplicated (D) | OMIM Number |
| SRY | Yp11 | 46,XY gonadal dysgenesis, Swyer syndrome (M) | 480000 |
| SF1 | 9q33 | 46,XY gonadal dysgenesis with adrenal failure | 184757 |
| DHH | 12q12-q13.1 | 46,XY gonadal dysgenesis (M) | 605423 |
Testis-determining genes are expressed in the developing gonad at the time of testis-determination. The expression of these genes can be detected by in situ hybridization or immunocytochemistry.
Genetic testing may be a useful aid for diagnosis, treatment and genetic counseling in cases of sex reversal. This should be considered once life-threatening conditions, such as congenital adrenal hyperplasia and adrenal hypoplasia congenita, have been excluded. Analysis is performed by PCR amplification of genomic DNA and, where appropriate, DNA sequencing. In some cases histological studies and participation of other family members may be helpful. Testing is provided for qualified patients and without charge for:
- 46,XX testicular DSD
- 46,XY DSD and 46,XY complete gonadal dysgenesis
- 46,XX ovotesticular DSD
For more information about genetic testing, contact:
Harry Ostrer, M.D. / Carole Oddoux, Ph.D.
Professor of Pediatrics, Pathology and Medicine
Director, Human Genetics Program
New York University School of Medicine
550 First Avenue, MSB 136
New York, NY 10016
Phone: 212-263-7596
Fax: 212-263-3477
New genes can be discovered by linkage analysis and positional cloning in familial cases of sex reversal. Typically, these present with multiple family members affected with 46,XY pure gonadal dysgenesis, 46,XY partial gonadal dysgenesis, 46,XX maleness and/or true hermaphroditism, or gonadal agenesis such as this family with multiple cases of complete partial gonadal dysgenesis. In this family, the gene was mapped to the proximal long arm of chromosome 5 using linkage analysis.
New genes can also be discovered by deletion mapping using comparative genomic hybridization in sporadic and familial cases of sex reversal and by mapping deletion breakpoints in cases with balanced translocations.
For more information about linkage analysis and comparative genomic hybridization, contact:
Harry Ostrer, M.D.
Human Genetics Program, MSB 136
NYU School of Medicine
550 First Avenue
New York, NY 10016
Phone: 212-263-7596
Fax: 212-263-3477
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