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Abstract/Summary
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<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>46,XX testicular disorder/difference of sex development (46,XX DSD) is a rare congenital condition, characterized by a combination of the typical female sex chromosome constitution, 46,XX, and a variable male phenotype. In the majority of individuals with 46,XX DSD, a Y chromosome segment containing the sex-determining region gene (<jats:italic>SRY)</jats:italic> has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (<jats:italic>n</jats:italic> = 11), male controls (46,XY; variable cohort sizes) and female controls (46,XX; variable cohort sizes), in addition to RNA sequencing and DNA methylation analysis on blood samples from males with Klinefelter syndrome (47,XXY, <jats:italic>n</jats:italic> = 22). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (<jats:italic>n</jats:italic> = 10).</jats:p>
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<jats:title>Results</jats:title>
<jats:p>We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (<jats:italic>n</jats:italic> = 1), (2) with short Yp arms (breakpoint at 2.7–2.8 Mb, <jats:italic>n</jats:italic> = 2), (3) with medium Yp arms (breakpoint at 7.3 Mb, <jats:italic>n</jats:italic> = 1), and (4) with long Yp arms (<jats:italic>n</jats:italic> = 7), including deletions of <jats:italic>AMELY</jats:italic>,<jats:italic> TBLY1</jats:italic> and in some cases <jats:italic>PRKY</jats:italic>. We also identified variable expression of the X-Y homologues <jats:italic>PRKY</jats:italic> and <jats:italic>PRKX</jats:italic>. The Y-chromosomal transcriptome and methylome reflected the Y chromosome segment lengths, while changes to autosomal and X-chromosomal regions indicated global effects. Furthermore, transcriptional changes tentatively correlated with phenotypic traits of 46,XX DSD, including reduced height, lean mass and testicular size.</jats:p>
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<jats:title>Conclusion</jats:title>
<jats:p>This study refines our understanding of the genetic composition in 46,XX DSD, describing the translocated Y chromosome segment in more detail than previously and linking variability herein to genome-wide changes in the transcriptome and methylome.</jats:p>
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