preprints.org > medicine and pharmacology > neuroscience and neurology > doi: 10.20944/preprints202403.1844.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 29 March 2024 / Approved: 29 March 2024 / Online: 29 March 2024 (10:27:34 CET)

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI) resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

Rett Syndrome, X Chromosome Inactivation, longitudinal modeling

Medicine and Pharmacology, Neuroscience and Neurology

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