Abstract
Deletion of the dosage sensitive gene NR0B1 encoding DAX1 on chromosome Xp21.2 results in congenital adrenal hypoplasia (AHC), whereas NR0B1 duplication in 46,XY individuals leads to gonadal dysgenesis and a female phenotype. We describe a 21-year-old 46,XY female manifesting primary amenorrhea, a small immature uterus, gonadal dysgenesis, and notably absent adrenal insufficiency with a submicroscopic (257 kb) deletion upstream of NR0B1. We hypothesize that loss of regulatory sequences may have resulted in position effect up-regulation of DAX1 expression, consistent with phenotypic consequences of NR0B1 duplication. We propose that this genomic region and by extension those surrounding the dosage sensitive SRY, SOX9, SF1, and WNT-4 genes, should be examined for copy-number variation in patients with sex reversal.
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Acknowledgments
We thank Drs A.L. Beaudet, M. Piasecka and A. Kram for helpful discussion and suggestions. We are grateful to the patient and her family for participation in these studies. Supported in part by grants from the National Institute of Child Health and Human Development (PO1 HD39420 to J.R.L.), the Mental Retardation Research Center (HD24064), and the Polish Ministry of Scientific Research and Information Technology Grant PBZ/KBN (122/P05/01-7 to P.S.).
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M. Smyk and J. S. Berg contributed equally to this work.
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Smyk, M., Berg, J.S., Pursley, A. et al. Male-to-female sex reversal associated with an ∼250 kb deletion upstream of NR0B1 (DAX1). Hum Genet 122, 63–70 (2007). https://doi.org/10.1007/s00439-007-0373-8
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DOI: https://doi.org/10.1007/s00439-007-0373-8