Male-to-female sex reversal associated with an ∼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.

The Role of Copy Number Variants in Disorders of Sex Development

“…A deletion upstream of NR0B1 was identified using a targeted CGH array associated with 46,XY sex reversal [Smyk et al, 2007]. White and colleagues [2011] used a SNP array, confirmed by MLPA, to identify a deletion downstream of GATA4 in a 46,XY gonadal dysgenesis patient.…”

47, XY, +der(Y),t(X;Y)(p21.1;p11.2): A unique case of XY sex reversal

“…Duplications of a 160 kb region (DSS) that includes DAX1 are associated with disruption of the process of male sex determination and testis formation, despite the presence of the Y chromosome and of the SRY gene, resulting in the development of a female phenotype. DAX1 antagonizes SRY action by acting as a transcriptional repressor and negatively regulating the steroidogenic factor 1 (SF1)-mediated transactivation of numerous genes involved in the development of the hypothalamic-pituitary-adrenal -gonadal axis and in the biosynthesis of steroid hormones and AMH [McElreavey and Fellous, 1999;Zenteno-Ruiz et al, 2001;Iyer and McCabe, 2004;Sanlaville et al, 2004;Niakan and McCabe, 2005;Karkanaki et al, 2007;McCabe, 2007;Smyk et al, 2007;Wilhelm et al, 2007]. This results in absence of testicular development and Wolffian duct derivatives but normal M€ ullerian structures (uterus, vagina) [Sanlaville et al, 2004].…”

“…Despite the better understanding of the genetic basis of human sexual development, a molecular diagnosis can be established in only 20-25% of disorders of sex development [Smyk et al, 2007;Biason-Lauber et al, 2009]. In humans, molecular alterations of several genes including SRY, SOX9, SF1, WNT-4, CBX2, and DMTR1 can lead to XY sex reversal [Veitia et al, 1998;Kanai et al, 2005;Karkanaki et al, 2007;Lin et al, 2007;Wilhelm et al, 2007;DiNapoli and Capel, 2008;Sim et al, 2008;Biason-Lauber et al, 2009].…”

Copy number variations and human genetic disease

“…First, and most important, is by altering the copy number of a gene or multiple contiguous genes that are dosage-sensitive [12]. Second, CNVs can have a 'position effect' wherein they alter the gene expression level of nearby dosage-sensitive genes [13][14][15][16]. Third, deletions can unmask either a recessive mutation or a functional polymorphism in the remaining undeleted allele [17].…”