The current state of diagnostic genetics for conditions affecting sex development

Abstract

Disorders of sex development (DSD), are a group of rare congenital conditions. Unlike 46, XX DSD where the cause is usually clear, identification of a cause of XY DSD is often unclear and may be attributed to a disorder of gonadal development, androgen synthesis or androgen action. Reaching a firm diagnosis is challenging and requires expertise within a framework that abides by the highest standards of clinical care. Whilst conditions associated with altered sex development have improved our fundamental understanding of sex and gonadal development, it is debatable whether this improvement in our understanding has improved the lives of people with DSD. Thus, there is a need for more emphasis on showing that a firm diagnosis for conditions associated with DSD is associated with a change in clinical practice that benefits the patient. With the rapid advances in diagnostic technology, there is also a need for clearer guidance on the relative merits of biochemical vs genetic evaluation. The standardization and harmonization of complex genetic and biochemical analyses for rare conditions are issues that require further guidance and it is probably that international networks and registries for rare conditions will facilitate the development of this framework.

Disorders of sex development in cats with different complements of sex chromosomes

“…This phenotype could suggest presence of a deletion in Y chromosome; however, our molecular study did not support this possibility. It is known from human medicine that a large proportion of XY DSD has unknown background; however, numerous candidate genes with potentially causative mutations have been described (Alhomaidah, McGowan, & Ahmed, 2017;Eggers et al, 2016;Flück & Pandey, 2014). In domestic mammals, causative mutations in XY DSD animals were only found in the Mullerian inhibiting substance type-2 receptor gene (MISR2), which is responsible for persistent Mullerian duct syndrome in Miniature Schnauzer dogs (Wu et al, 2009) and in the androgen receptor gene (AR), where it causes androgen insensitivity syndrome in horses (Bolzon et al, 2016;Révay, Villagómez, Brewer, Chenier, & King, 2012;Welsford et al, 2017).…”

Oligogenic Origin of Differences of Sex Development in Humans

“…In the past, much has been learned about human sex development from monogenic disorders/differences of sex development (DSD), but the broad spectrum of phenotypes in numerous DSD individuals remains a conundrum. Currently, the genetic cause of less than 50% of DSD individuals has been solved [2,3]. Oligogenic disease has been proposed.…”

Genetic testing of XY newborns with a suspected disorder of sex development

“…Thus, as a group, 46, XY neonates with atypical genitalia represent the greatest challenge in terms of diagnosis and long-term management. Whilst clinical guidelines stress the importance of an integrated multidisciplinary approach for the assessment and management of these conditions [1,11], rapid advances in genetic knowledge as well as technology are altering the stepwise investigational strategies that have traditionally been employed in this field [12,13]. This review will focus on the neonatal presentation of DSD and summarise the current approach to the evaluation of these children.…”