The Genetics of Disorders of Sex Development in Humans

Abstract

One of the defining events during human embryonic development with the most far-reaching effects for the individual is whether the embryo develops as male or female. The crucial step in this process is the differentiation of the bipotential embryonic gonads into either testes or ovaries. If the embryo inherits X and Y sex chromosomes, the Y-linked SRY (sex determining region in Y) gene initiates a network of genes that results in a functional testis and ultimately a male phenotype. By contrast, in an embryo with 2 X chromosomes, the undifferentiated gonad develops as an ovary resulting in a female phenotype. Perturbation of any of the genes in either the testicular or ovarian developmental pathway can result in individuals with disorders of sex development. In this review, we provide a summary of known components of testicular or ovarian pathways and their antagonistic actions and give a brief overview of new technologies currently used to identify the missing pieces of the sex development network.

Sex Reversal in Reptiles: Reproductive Oddity or Powerful Driver of Evolutionary Change?

“…These species have relatively stable sex chromosomes that are strongly differentiated, and the extrinsic environment has little or no influence over sex determination. This has led to a somewhat biased view that sex reversal occurs only as a genetic aberration through mutational processes [Eggers et al, 2014;Ohnesorg et al, 2014]. However, sex reversal can occur through both mutations and environmental influence over genes in the sex determination and/or sex differentiation cascade, the latter being the focus of this review.…”

Disorders of sex development: advances in genetic diagnosis and challenges in management

“…5,6 The transcriptional activation by SRY and NR5A1 is mediated by the binding of these two proteins to the testis-specific enhancer of SOX9 core (TESCO) region, which lies approximately 13 kb upstream of SOX9. 7 Once SOX9 levels reach a critical threshold, several positive regulatory loops are initiated, including autoregulation of SOX9 expression and formation of feed-forward loops via FGF9 or PGD2 signaling. 5,6 During testicular development, SOX9 functions, by regulating the production of AMH from Sertoli cells, and possibly by repressing genes involved in ovarian development such as WNT4 and FOXL2.…”

“…Therefore, when ectopically expressed, it might substitute for SRY in driving testicular development. 7 In addition, a probable regulatory element lying downstream of the GATA4 gene was identified when a 35 kb deletion was detected in a person with 46,XY complete gonadal dysgenesis. 17 Similarly, in those with 46,XY DSD, microarray analysis detected an intragenic deletion of WWOX 18 and a deletion at least 42 kb upstream of the DMRT1 gene.…”

“…19 In fact, array analyses have now identified many DNA duplications and deletions in people with DSD, several of which are located close to known sex development genes and are suspected to have caused disruption of gene regulatory regions. 7 It is clear, therefore, that there is potential for disruption of the sex organ differentiation process at multiple different stages. The clinical phenotype will depend on the nature of disruption.…”

Using ROADMAP Data to Identify Enhancers Associated with Disorders of Sex Development

“…This promoter was chosen due to its small size (52 bp) and very low background activity [Yee and Rigby, 1993]. We decided to test these constructs for basal enhancer activity as well as responsiveness to NR5A1, SRY, and SOX9, 3 transcription factors known to activate expression of several testicular genes [reviewed in Ohnesorg et al, 2014].…”