Male-to-female sex reversal associated with an ∼250 kb deletion upstream of NR0B1 (DAX1)

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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.