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Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome

Merritt, Jonathan K ; Fang, Xiaolan ; Caylor, Raymond C ; Skinner, Steven A ; Friez, Michael J ; Percy, Alan K ; Neul, Jeffrey L

Genes, 2024-05, Vol.15 (5), p.594 [Periódico revisado por pares]

Switzerland: MDPI AG

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Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome
Autor: Merritt, Jonathan K ; Fang, Xiaolan ; Caylor, Raymond C ; Skinner, Steven A ; Friez, Michael J ; Percy, Alan K ; Neul, Jeffrey L
Assuntos: Adolescent ; Adult ; Age ; Alleles ; Child ; Child, Preschool ; Chromosomes, Human, X - genetics ; Diseases ; Female ; Females ; Genetic research ; Genotype ; Genotype & phenotype ; Genotypes ; Humans ; longitudinal modeling ; Male ; MeCP2 protein ; Methyl-CpG binding protein ; Methyl-CpG-Binding Protein 2 - genetics ; Neurodevelopmental disorders ; Rett syndrome ; Rett Syndrome - genetics ; Rett Syndrome - pathology ; Scoliosis ; Severity of Illness Index ; X chromosome inactivation ; X Chromosome Inactivation - genetics ; X chromosomes ; Young Adult
É parte de: Genes, 2024-05, Vol.15 (5), p.594
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene ( ). Most often, the disease causing the 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 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 genotype with a correlation between XCI and severity observed only in individuals with 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.
Editor: Switzerland: MDPI AG
Idioma: Inglês

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Normalized Clinical Severity Scores Reveal a Correlation between X Chromosome Inactivation and Disease Severity in Rett Syndrome

Merritt, Jonathan K ; Fang, Xiaolan ; Caylor, Raymond C ; Skinner, Steven A ; Friez, Michael J ; Percy, Alan K ; Neul, Jeffrey L

Switzerland: MDPI AG

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