Gene dosage effects in 46, XY DSD: usefulness of CGH technologies for diagnosis.

Abstract

In 46, XY individuals, the testicular development is initiated by the expression of SRY, which sets into motion a chain of signal transduction events leading to development of the male external and internal genitalia. In the absence of SRY, ovarian development occurs, associated with a female phenotype [1]. Disorders of Sex Development (DSD) are a range of congenital conditions of atypical gonadal development leading to discordance between chromosomal, gonadal and phenotypic sex. According to the Chicago consensus [2], DSD are divided in three categories based on karyotype: 46, XX DSD, 46, XY DSD and sex chromosome DSD. Although there have been considerable advances in our understanding of the genetic factors and mechanisms involved in gonadal differentiation in the last 10 years [3], a molecular diagnosis is made in only around 20 % of cases of DSD, except in cases where the biochemical profile indicates a specific steroidogenic block [2]. In 46, XY DSD with disorders of gonadal development, individuals with complete gonadal dysgenesis are phenotypically females with streak gonads and are often diagnosed because of primary amenorrhea whereas, in individuals with partial gonadal dysgenesis, the phenotype is more ambiguous. Approximately 15 % of all cases of gonadal dysgenesis carry inactivating mutations in SRY, with the majority localized within the HMG-domain [4]. Rare cases of gonadal dysgenesis with small interstitial deletions outside the SRY-open reading frame have been described [5]. When SRY function is normal, other genes are known to be involved in the occurrence of 46, XY DSD gonadal dysgenesis, with a loss-of-function (for example SOX9, WT1, NR5A1/SF1, DMRT1, MAP3K1) or with a gain-of-function (for example WNT4 and NR0B1/DAX1) [1, 6]. Nevertheless, the underlying genetic basis of complete gonadal dysgenesis is unknown in about 50 % of the patients [7]. As many of the genes involved in gonadal development have a dosage effect, DSD may be caused by copy-number variations (CNVs) corresponding to deletions or duplications of these genes [8]. Conventional karyotype may not be adequate to detect these changes but array-CGH has been emerging as a powerful tool to identify submicroscopic CNVs on a genome wide scale.