7972 A Shared Phenotype, Transcriptome, and Methylome in Turner Syndrome Across Various Karyotypes with Concurrent Chronic Neutrophil Activation

Abstract Disclosure: J. Just: None. L. Ridder: None. E. Johannsen: None. H. Christensen: None. A. Skakkebæk: None. C.H. Gravholt: None. Turner syndrome (TS) is a clinical diagnosis with a karyotype containing one X chromosome and complete or partial absence of the second X chromosome. TS is typically associated with clinical manifestations such as short stature, hypergonadotropic hypogonadism and metabolic conditions. The genome-wide changes in females with TS affect both transcriptome and methylome. Historically, genomic studies have primarily focused on the 45,X karyotype, leaving the impact of other karyotypes unexplored. Only 35-45% of the entire TS population has the 45,X karyotype, while the remaining TS women have a range of other karyotypes - i.e. 45,X/46,XX, 46,X,i(Xq), 46,X,i(Xp), 45,X/46,XY, ring X. This study aimed to bridge this gap by comparing TS individuals with the standard 45,X karyotype (TS 45,X) (n = 32) to those with alternative karyotypic forms (TS other karyotypes) (n = 24), alongside age-matched 46,XX controls (n = 33). Specifically, we analyzed the DNA methylation and gene expression profiles from whole-blood samples and explored the genetic and clinical similarities between these groups. Overall findings revealed a shared phenotype and an identical autosomal transcriptome and methylome between TS 45,X and TS other karyotypes. Furthermore, TS 45,X and TS other karyotypes shared the same expression profile for all pseudoautosomal 1 (PAR1) genes on the X chromosome. In addition, the expression of XIST from the q-arm of the X chromosome did not affect the autosomal transcriptome or methylome. Thus, the X chromosomal p-arm, and perhaps in particular PAR1, appear to be a main driver influencing the genome-wide transcriptome and methylome Combining DNA methylation, gene expression and white blood cell counts, we observed a higher neutrophil count (p < 0.01), and increased neutrophil activation in the combined TS group. The increased neutrophil activity, based on increased gene expression of neutrophil activation markers (myeloperoxidase, neutrophil elastase, S100A8/9, p < 0.01), suggested a pathological activation of neutrophils with concomitant release of pro-inflammatory mediators. We further validated the increase of neutrophils in TS women in an independent cohort using flow cytometry (p < 0.01). Emerging evidence has highlighted the substantial involvement of neutrophils in chronic inflammatory processes associated with metabolic diseases such as obesity and diabetes, which triggers a sustained low-grade inflammation partially driven by activated neutrophils. The neutrophil increase and activation in TS women may offer an explanation for this phenotypic trait observed in TS women. Therefore, identifying TS women with increased neutrophil activation in order to initiate anti-inflammatory treatment earlier could potentially mitigate the progression towards more severe metabolic disturbances and associated co-morbidities. Presentation: 6/1/2024