title: Male-to-female sex reversal associated with an approximately 250 kb deletion upstream of NR0B1 (DAX1).
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Smyk
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.forename: Amber
authors.initials: A
authors.lastname: Pursley
authors.forename: Fiona K
authors.initials: FK
authors.lastname: Curtis
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Fernandez
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Bien-Willner
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000328:Adult; D001483:Base Sequence; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D012734:Disorders of Sex Development; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins