Genetic testing is an integral part of the evaluation of patients with disorders of sex development (DSD), and the arrival of whole-exome sequencing in the clinic has the potential to greatly facilitate the diagnosis of DSD. However, several barriers prevent this approach from reaching its full clinical potential. Our incomplete knowledge of both the genes and the specific variants associated with DSD impairs our ability to recognize pathogenic mutations. Despite growing evidence that mutations in DSD genes can produce a broad spectrum of phenotypes, current guidelines recommend restricting the evaluation for DSD to severe cases of undervirilization or overvirilization, resulting in potential missed opportunities both for diagnosis and for understanding the full range of genotype-phenotype associations for DSD genes. Psychosocial outcomes of genetic testing have been understudied in patients and families affected by DSD, and while whole-exome sequencing has the potential to provide valuable diagnostic information, it may not produce a clear diagnosis in many cases and has the potential to add to anxiety and stress. This project will address these barriers by applying and evaluating whole-exome sequencing in subjects with DSD and related conditions.
Aim 1 of this project uses whole-exome sequencing both in patients with ?textbook? presentations of DSD as well as in patients with an expanded spectrum of presentations of apparent undervirilization (such as hypospadias with or without bifid scrotum) or apparent overvirilization (such as isolated clitoromegaly).
Aim 2 of this project assesses the impact of returning genetic testing results on parents using a series of validated measures, including assessments of anxiety, stress, expectations, and utility. These studies will provide essential information to direct the use of whole-exome sequencing in the clinical care of patients with broad range of conditions that result in apparent over/undervirilization.
Genetic testing is commonly performed for children with disorders of sex development, but we do not fully understand the genetics of these conditions or the impact of genetic testing on patients and families. In this study, we will identify genetic causes of a broad range of conditions that affect sex development by using whole-exome sequencing, which allows all human genes to be examined in a single test, and we will assess the psychological impact on parents of receiving the results of genetic testing. The results from our study will improve our ability to use genetic testing effectively in the care of patients and families affected by these conditions.
| Swartz, Jonathan M; Ciarlo, Ryan; Guo, Michael H et al. (2017) A 46,XX Ovotesticular Disorder of Sex Development Likely Caused by a Steroidogenic Factor-1 (NR5A1) Variant. Horm Res Paediatr 87:191-195 |
| Swartz, J M; Ciarlo, R; Denhoff, E et al. (2017) Variation in the clinical and genetic evaluation of undervirilized boys with bifid scrotum and hypospadias. J Pediatr Urol 13:293.e1-293.e6 |
| Kremen, Jessica; Chan, Yee-Ming; Swartz, Jonathan M (2017) Recent findings on the genetics of disorders of sex development. Curr Opin Urol 27:1-6 |
| Swartz, Jonathan M; Ciarlo, Ryan; Guo, Michael H et al. (2017) Two Unrelated Undervirilized 46,XY Males with Inherited NR5A1 Variants Identified by Whole-Exome Sequencing. Horm Res Paediatr 87:264-270 |
