title: Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome.
abstract: We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.
authors.affiliation: Institute of Child Health, University College London, London, UK. t.charman@ich.ucl.ac.uk
authors.forename: Tony
authors.initials: T
authors.lastname: Charman
authors.forename: Tracey C S
authors.initials: TC
authors.lastname: Neilson
authors.forename: Veronica
authors.initials: V
authors.lastname: Mash
authors.forename: Hayley
authors.initials: H
authors.lastname: Archer
authors.forename: Mary T
authors.initials: MT
authors.lastname: Gardiner
authors.forename: Gun P S
authors.initials: GP
authors.lastname: Knudsen
authors.forename: Aoibhinn
authors.initials: A
authors.lastname: McDonnell
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Perry
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Whatley
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Mount
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hastings
authors.forename: Maj
authors.initials: M
authors.lastname: Hulten
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Orstavik
authors.forename: Sheena
authors.initials: S
authors.lastname: Reilly
authors.forename: Hilary
authors.initials: H
authors.lastname: Cass
authors.forename: Angus
authors.initials: A
authors.lastname: Clarke
authors.forename: Alison M
authors.initials: AM
authors.lastname: Kerr
authors.forename: Mark E S
authors.initials: ME
authors.lastname: Bailey
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D051783:Methyl-CpG-Binding Protein 2; D020125:Mutation, Missense; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins