Genotype-phenotype correlation in Brazillian Rett syndrome patients

Abstract

-Background: Rett syndrome (RS) is a severe neurodevelopmental X-linked dominant disorder caused by mutations in the MECP2 gene. Purpose: To search for point mutations on the MECP2 gene and to establish a correlation between the main point mutations found and the phenotype. Method: Clinical evaluation of 105 patients, following a standard protocol. Detection of point mutations on the MECP2 gene was performed on peripheral blood DNA by sequencing the coding region of the gene. Results: Classical RS was seen in 68% of the patients. Pathogenic point mutations were found in 64.1% of all patients and in 70.42% of those with the classical phenotype. Four new sequence variations were found, and their nature suggests patogenicity. Genotype-phenotype correlations were performed. Conclusion: Detailed clinical descriptions and identification of the underlying genetic alterations of this Brazilian RS population add to our knowledge of genotype/ phenotype correlations, guiding the implementation of mutation searching programs.KEY WORDS: Rett syndrome, genotype-phenotype correlation.correlação genótipo-fenótipo em pacientes brasileiras com síndrome de rett resumo -Introdução: A síndrome de Rett é uma grave doença do neurodesenvolvimento ligada ao X dominante, causada por mutações no gene MECP2. Objetivos: Identificar mutações de ponto no gene MECP2 e estabelecer uma correlação entre as principais mutações encontradas e o fenótipo. Método: Avaliação clínica de 105 pacientes, seguindo um protocolo estabelecido. A identificação de mutações de ponto foi realizada em DNA de sangue periférico por sequenciamento da região codificante do gene amplificada por PCR. Resultados: Em 68% dos pacientes observou-se o quadro clássico da síndrome. Mutações de ponto patogênicas foram encontradas em 64,1% dos pacientes e em 70,42% das pacientes com o quadro clássico. Quatro novas variações de seqüência foram identificadas e sua natureza sugere patogenicidade. Correlações genótipo-fenótipo foram estabelecidas. Conclusão: Descrições clínicas detalhadas desta população brasileira de pacientes acrescenta conhecimento às correlações genótipo-fenótipo nesta grave condição, que podem auxiliar na implantação de programas de triagem de mutações. PALAVRAS-CHAVE: síndrome de Rett, correlações genótipo-fenótipo.

Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X

“…Differences in apnea incidence and respiratory irregularity between mutation types suggest that the respiratory phenotypes are closely coupled to the functions of MeCP2. While breathing problems are reported to be common in patients with both T158M and R168X mutations (de Lima FT, 2009) (Halbach et al, 2012), a distinction with respect to severity has not been documented in clinical studies.…”

Altered Attainment of Developmental Milestones Influences the Age of Diagnosis of Rett Syndrome

“…Our findings are supported by previous literature, which has also found that individuals with p.R133C, p.R294X, and Cterminal deletions were generally less severe, had greater ambulatory skills, and were also more likely to have learned to talk and maintain the ability. 5,12,13,[22][23][24] Those with p.R306C have been found to be more mobile, 13 yet often not acquiring the ability to talk. 13,23 A later onset of regression has previously been described for those with p.R133C, p.R294X mutations, and C-terminal deletions.…”

“…5,12,13,[22][23][24] Those with p.R306C have been found to be more mobile, 13 yet often not acquiring the ability to talk. 13,23 A later onset of regression has previously been described for those with p.R133C, p.R294X mutations, and C-terminal deletions. 12 The most severe phenotypes have been associated with the p.R255X, p.R168X, or p.R270X mutations, which have been shown more likely to exhibit problems after birth and less likely to have learned to walk or talk.…”

“…12 The most severe phenotypes have been associated with the p.R255X, p.R168X, or p.R270X mutations, which have been shown more likely to exhibit problems after birth and less likely to have learned to walk or talk. 5,12,13,22,23 They also have an earlier onset of regression and stereotypies, which may explain their younger diagnosis. In contrast to previous research, which generally found cases with large deletions more severe, 13,24 we were surprised that 7/16 cases with large deletions did achieve the 3 developmental milestones: ability to sit, walk, babble, and use words.…”

Atypical presentations and specific genotypes are associated with a delay in diagnosis in females with Rett syndrome

“…Investigations of relationships between phenotype severity and genotype have found that individuals with p.R133C, p.R294X and p.R306C have been reported to have delayed onset of regression, later onset of stereotypies, more retention of words and hand function, and to have learnt to walk [Leonard et al, 2003; Colvin et al, 2004; Charman et al, 2005; Bebbington et al, 2008; Neul, 2008; de Lima et al, 2009]. The more severe phenotypes are found in individuals with p.R255X, p.R270X and p.R168X, who were more likely to have a younger age of regression, loss of social interaction and onset of stereotypies.…”