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.

Rett syndrome with and without detected MECP2 mutations: An attempt to redefine phenotypes

“…Epilepsy was present in 70.4% of the cases. Among patients with the severe form, 81,4% had truncating mutations, and all but one with the R168X mutation presented it; they showed a median severity score of 15 (range, [12][13][14][15][16][17][18][19][20].…”

“…Concerning the phenotype of specific mutations, several studies [14][15][16][17] showed that patients with the R133C and R306C mutations have better overall function. In general, the most severe outcomes were found with the R270X and R255X mutations [11,16].…”

“…Concerning the phenotype of specific mutations, several studies [14][15][16][17] showed that patients with the R133C and R306C mutations have better overall function. In general, the most severe outcomes were found with the R270X and R255X mutations [11,16]. Mutations toward the N terminus, including T158M and R168X, were also associated with a more severe phenotype [12,17]; however, no specific neurological or behavioural findings were identified in patients with these mutations, with the exception of an association of fear and anxiety with R133C and R306C [18], and mood abnormalities in patients with R294X [16].…”

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

“…19 Control samples used in statistical comparisons were 49 previously analysed (Knudsen et al, unpublished) healthy females age 19 -63 years (for buccal cell XCI data) and 153 normal healthy females (for blood XCI data), of whom 117 were anonymised blood donors (age 19 -55 years) and 36 were sampled from the set of individuals used in the buccal control set (age 19 -55).…”

Italian Rett database and biobank

“…At present, all clinical details except for the general classification in classic, variant, or RTT-like cases, are available only for bank curators on the '' Additional info'', page. We are planning to create, for each case, a table with a set of clinical features and a related clinical score according to data in the literature [Charman et al, 2005;Colvin et al, 2003;Huppke et al, 2002;Kerr et al, 2001;Monros et al, 2001]. The new schedule will be freely available to the general public.…”