Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Abstract

BackgroundDisorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.ResultsWe analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.ConclusionsOur massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1105-y) contains supplementary material, which is available to authorized users.

GATA4 variant identified by whole‐exome sequencing in a Japanese family with atrial septal defect: Implications for male sex development

“…This would primarily be consistent with the GATA4 variant in this family, because previous studies have shown that GATA4 variants, though they are occasionally accompanied by extra‐cardiac features such as 46,XY DSD6, 7 and congenital diaphragmatic hernia,14 usually lead to isolated CHDs (primarily ASD2). However, lack of extra‐cardiac features is not a common finding in CHDs in general.…”

“…Thus, the deleterious effect of GATA4 p.(R284H) variant on testicular function would remain at a subclinical level, if any. It should be pointed out, however, that GATA4 variants have been identified in five patients with 46,XY DSD 6, 7. Thus, it is likely that GATA4 variants lead to 46,XY DSD in rather exceptional subjects, depending on the residual activity of the GATA4 variants and the predisposing genetic and environmental factors of the variant‐positive subjects.…”

“…GATA4 variants have been identified not only in patients with ASD but also in those with various types of CHDs including tetralogy of Fallot (TOF), ventricular septal defect, and atrioventricular septal defect 5, 6. Furthermore, consistent with the wide expression pattern including the testis, GATA4 variants have also been found in patients with 46,XY disorder of sex development (DSD) due to impaired testis formation with or without CHD 6, 7. These findings imply that GATA4 variants lead to the development of various types of CHD and 46,XY DSD with variable expressivity and reduced penetrance.…”

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases

“…The postulated mechanisms of interaction between the Wnt and AMH pathway are shown in Figure 9 . Modern methods of genetic investigation [Bashamboo et al, 2010;Eggers et al, 2016] applied to idiopathic PMDS will probably produce unexpected results. In the meantime, identified mutations of the AMH and AMHRII genes in PMDS are invaluable probes for understanding the biosynthesis and mechanism of action of a gonadal hormone, which in addition to playing a key role in male sex differentiation, is gaining recognition as an important factor in female reproduction.…”

The Role of Copy Number Variants in Disorders of Sex Development

“…variants is undoubtedly important; a recent large-scale analysis of DSD patients using a targeted next-generation sequencing panel revealed a diagnosis in 43% of 46,XY DSD cases [Eggers et al, 2016]. However, these studies did not focus on copy number variants (CNVs), hence a significant proportion of the unsolved DSD cases could be due to CNVs that impact coding and especially noncoding regions.…”