Abstract
BackgroundDisorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes.MethodsTo investigate the relevance of these VUS in regards to the patient’s phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (YPOS) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-YB6 and undervirilized B6-YPOS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-YPOS males).ResultsWe identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-YPOS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9.ConclusionThe use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation.
Highlights
Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia
We show that the identified 15 novel candidate genes contain a variants of unknown clinical significance (VUS) identified in 46,XY DSD cases and are expressed at the time of sex development in a sex-differential manner
We focused on variants identified in genes underexpressed in B6-Y chromosome from the poschiavinus strain (YPOS) males whose higher expression in WT males correlated with normal male sex development
Summary
Disorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. Mostly under the influence of testicular (e.g., testosterone, AMH) or ovarian (e.g., estradiol) hormones or transcription factors (e.g., COUP-TFII) that further differentiate the body into typical male or female structures, including both internal and external genitalia [3, 4]. The umbrella term DSD encompasses conditions ranging from mild hypospadias (abnormal location of the meatus) to discrepancy between sex chromosomes and external genital phenotype (formerly known as sex reversal, either complete or with ambiguous genitalia). The birth of a child with a DSD may be highly stressful for families, bringing uncertainty in regard to the child’s future psychosexual development and clinical management [8, 10, 11]
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