Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Biol Sex Differ. 2024 Oct 8;15(1):77. doi: 10.1186/s13293-024-00654-8.
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 (SRY) has been translocated to the paternal X chromosome. However, the precise genomic content of the translocated segment and the genome-wide effects remain elusive.
We performed long-read DNA sequencing, RNA sequencing and DNA methylation analyses on blood samples from 46,XX DSD (n = 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, n = 22). We also performed clinical measurements on all 46,XX DSD and a subset of 46,XY (n = 10).
We identified variation in the translocated Y chromosome segments, enabling subcategorization into 46,XX DSD (1) lacking Y chromosome material (n = 1), (2) with short Yp arms (breakpoint at 2.7-2.8 Mb, n = 2), (3) with medium Yp arms (breakpoint at 7.3 Mb, n = 1), and (4) with long Yp arms (n = 7), including deletions of AMELY, TBLY1 and in some cases PRKY. We also identified variable expression of the X-Y homologues PRKY and PRKX. 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.
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.
46,XX 睾丸发育障碍/性发育差异（46,XX DSD）是一种罕见的先天性疾病，其特征是典型的女性性染色体组成 46,XX 与可变的男性表型相结合。在大多数 46,XX DSD 个体中，包含性别决定区基因（SRY）的 Y 染色体片段已易位到父系 X 染色体上。然而，易位片段的精确基因组内容和全基因组效应仍不清楚。
我们对来自 46,XX DSD（n=11）、男性对照（46,XY；不同大小的可变队列）和女性对照（46,XX；不同大小的可变队列）的血液样本进行了长读 DNA 测序、RNA 测序和 DNA 甲基化分析，以及对来自 Klinefelter 综合征（47,XXY，n=22）男性的血液样本进行了 RNA 测序和 DNA 甲基化分析。我们还对所有 46,XX DSD 和一部分 46,XY（n=10）进行了临床测量。
我们发现了易位 Y 染色体片段的变异，能够将 46,XX DSD 进一步分为 46,XX DSD（1）缺乏 Y 染色体物质（n=1）、（2）短 Yp 臂（断裂点在 2.7-2.8 Mb，n=2）、（3）中 Yp 臂（断裂点在 7.3 Mb，n=1）和（4）长 Yp 臂（n=7），包括 AMELY、TBLY1 的缺失，在某些情况下还包括 PRKY 的缺失。我们还发现了 X-Y 同源物 PRKY 和 PRKX 的可变表达。Y 染色体转录组和甲基组反映了 Y 染色体片段的长度，而常染色体和 X 染色体区域的变化表明存在全基因组效应。此外，转录变化与 46,XX DSD 的表型特征之间存在相关性，包括身高降低、瘦体重减少和睾丸体积减小。
本研究进一步了解了 46,XX DSD 的遗传组成，比以前更详细地描述了易位的 Y 染色体片段，并将其变异性与转录组和甲基组的全基因组变化联系起来。
