ESPE2024 Top 20 Posters Top 20 Posters (19 abstracts)
DNA methylation level at five specific CG-sites within TRAK1 correlates with the neurocognitive profile in individuals with Klinefelter syndrome.
Helene Bandsholm Leere Tallaksen 1 , Emma B. Johannsen 1 , Joel Berletch 2 , Xinxian Deng 2 , Gala Filippova 2 , Claus H. Gravholt 1 , Christine Disteche 2 , Jesper Just 1 & Anne Skakkebæk 1
1Aarhus University Hospital, Aarhus, Denmark. 2University of Washington, Seattle, USA
Background: Klinefelter syndrome (47,XXY; KS) influences neurodevelopment, resulting in a neurocognitive profile with a more pronounced impact on verbal IQ compared to performance IQ. Additionally, KS is linked to changes in the epigenome and transcriptome. The relation between these epigenetic and genetic changes and the neurocognitive phenotype has yet to be determined.
Methods: We conducted a comprehensive and integrative analysis of the neurocognitive profile and methylome in peripheral blood samples from cohort 1, consisting of 64 males with KS and 65 control males. These findings were validated in cohort 2, comprising 22 males with KS and 16 control males, who additionally provided transcriptome data. The results were further validated in neural precursor cells derived from human induced pluripotent stem cells from 47,XXY and 46,XY amniotic cells.
Results: We identified correlations between the methylation level at five CG-sites within TRAK1 and various neurocognitive measures, including verbal IQ and performance IQ, in males with KS. In cohort 1, these CG-sites were found to be hypomethylated in KS compared to controls. A similar methylation pattern was observed in cohort 2, where we found that the methylation level at these CG-sites correlated with the RNA expression level of a specific TRAK1 transcript, ENST00000341421.7. Compared to 46,XY cells, hypomethylation at these CG-sites and upregulation of ENST00000341421.7 were observed in the 47,XXY neural precursor cells. We developed a model capable of predicting the full-scale IQ in males with KS, based on the methylation level at the five CG-sites within TRAK1.
Conclusion: We demonstrate that the methylation level at five specific CG-sites within TRAK1 in males with KS is associated with their neurocognitive phenotype, suggesting a genetic underpinning for the neurocognitive challenges observed in KS.
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