ArticleBiology of sex differences2024
Integration of long-read sequencing, DNA methylation and gene expression reveals heterogeneity in Y chromosome segment lengths in phenotypic males with 46,XX testicular disorder/difference of sex development.
Article in Biology of sex differences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.
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Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Sex chromosome aneuploidy impacts on human gene expression and regulation: a systematic review.Molecular medicine (Cambridge, Mass.) · 2025Pooled it
- Combined optical genome mapping and cnv-seq identify complex Y-chromosome rearrangements and ectopy in 46,XX testicular disorder of sex development.Molecular cytogenetics · 2026Article
- Neurocognitive function in males with 46,XX testicular difference of sex development.Orphanet journal of rare diseases · 2025Article
- Reliable detection of sex chromosome abnormalities by quantitative fluorescence polymerase chain reaction.Clinical chemistry and laboratory medicine · 2025Article
- X and Y gene dosage effects are primary contributors to human sexual dimorphism: The case of height.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Gene therapy for disorders of sex development: current applications and future challenges.Frontiers in genetics · 2025Review
Corrections and comments
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Authors and funding
14 authors.
Funding
Abstract
background46,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.
methodsWe 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).
resultsWe 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.
conclusionThis 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.
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