Review disorders of sex development: The evolving role of genomics in diagnosis and gene discovery

Abstract

Disorders of Sex Development (DSDs) are a major paediatric concern and are estimated to occur in around 1.7% of all live births (Fausto‐Sterling, Sexing the Body: Gender Politics and the Construction of Sexuality, Basic Books, New York, 2000). They are often caused by the breakdown in the complex genetic mechanisms that underlie gonadal development and differentiation. Having a genetic diagnosis can be important for patients with a DSD: it can increase acceptance of a disorder often surrounded by stigma, alter clinical management and it can assist in reproductive planning. While Massively Parallel Sequencing (MPS) is advancing the genetic diagnosis of rare Mendelian disorders, it is not yet clear which MPS assay is best suited for the clinical diagnosis of DSD patients and to what extent other established methods are still relevant. To complicate matters, DSDs represent a wide spectrum of disorders caused by an array of different genetic changes, many of which are yet unknown. Here we discuss the different genetic lesions that are known to contribute to different DSDs, and review the utility of a range of MPS approaches for diagnosing DSD patients. Birth Defects Research (Part C) 108:337–350, 2016. © 2016 Wiley Periodicals, Inc.

Clinical utility of early rapid genome sequencing in the evaluation of patients with differences of sex development

“…Genome sequencing, in contrast, analyzes noncoding deep intronic and intergenic regions as well, where it is postulated that many undiagnosed variants involving transcriptional and translational regulatory elements of key DSD genes are located (Baetens et al, 2017;Harrison et al, 2013;Migale et al, 2021;Sutton et al, 2011;White et al, 2011). Variants in noncoding regulatory regions associated with SOX9, SOX3, NR0B1, and GAT4 have all been implicated in differential gonadal development and (Atlas et al, 2021;Benko et al, 2011;Croft et al, 2016;Croft, Ohnesorg, Hewitt, et al, 2018;Harrison et al, 2013;Harrison et al, 2014;Kim et al, 2015;Smyk et al, 2007;Sutton et al, 2011). Moreover, by avoiding selective sequence capture, GS provides more uniform read depth, and therefore, more accurate sequencing capability than ES, even in detecting exome variants (Belkadi et al, 2015;Meynert et al, 2014).…”

Queering genomics: How cisnormativity undermines genomic science

“…Concurrent with these developments, the field of clinical genomics has experienced a rapid period of growth and change as next-generation sequencing data have become more precise, accurate, and affordable. 31 , 32 , 33 , 34 As the ability to identify and name chromosomal and single-gene contributions to sex characteristics has grown, genomics has become more useful in labeling the molecular mechanisms underlying sex characteristics, including some variations in sex characteristics that have clear medical implications. For example, studies have shown that gonadoblastoma risk varies considerably depending on molecular diagnosis, that most gonadal tumors develop during or after puberty, and that acute health problems (such as urinary obstruction or adrenal crisis in congenital adrenal hyperplasia) can be addressed in infancy or early childhood without making irreversible changes to a child’s anatomy.…”

Genetics of human sexual development and related disorders

“…The expression of the SRY gene in pre-Sertoli cells works as a switch that guides the initial gonadal determination to the testicular fate, and together with NR5A1, triggers the testis development programme through activation and maintenance of the SOX9 signalling pathway. Other important genes for the early testis development are NR0B1 (Nuclear Receptor subfamily 0 group B member 1), AMH (Anti-Mullerian Hormone) and GATA4 and its co-factor FOG2 (Friend of GATA 2) [30]. At this time point, the Wolffian and the M€ ullerian duct precursor systems coexist [31].…”