Research Awards
Tony Charman, Ph.D.
Institute of Child Health, London, UK
"A Detailed Genotype-Phenotype Correlation Study in Rett Syndrome"
2-Year Award: $99,437 Research Sponsor: Family Friends of Jessie Lebson
Final Report (November 2004)
A detailed genotype-phenotype correlation study in Rett syndrome
This study aimed to examine associations between the type and position of mutations in the MECP2 gene and clinical characteristics in a large cohort of patients from the UK with Rett syndrome, specifically attempting to recruit a large number of 'atypical' cases who may be most informative in terms of establishing such associations. We adopted a novel approach to dissecting genotype-phenotype relationships (focusing on just 3 main aspects, or 'dimensions', of the phenotype - the 'typicality' of the disorder, the severity and the age-of-onset) and to subdividing groups of mutations (missense, early truncating and late truncating groupings only). Effects of individual mutations on phenotype were also examined, as was the effect of X chromosome inactivation (XCI) ratio.
We recruited 191 families to the study. This included 140 cases with classic Rett syndrome and 51 cases with atypical Rett syndrome. 135 cases had identified mutations in MECP2.
The main findings were that cases with early onset of regression and seizures, and those with clinical features that might indicate alternative causes of the disorder, were more likely to have no identified 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. It was confirmed that different common individual mutations were associated with more severe and less severe presentations. There was evidence suggesting that the X-inactivation ratio (XCI) moderated the effect of genotype on phenotype.
In summary, the approach we used allowed us to identify novel genotype-phenotype associations that may aid our understanding of the pathogenesis of Rett syndrome and also contribute to clinical knowledge.
We hope that information from this study will help both families and doctors of Rett syndrome patients around the world in their understanding of how the degree of severity of the disorder is related to the underlying genetic cause in individual patients.
Tony Charman, Ph.D.Institute of Child Health, London, UK
"A Detailed Genotype-Phenotype Correlation Study in Rett Syndrome"
2-Year Award: $99,437 Research Sponsor: Family Friends of Jessie Lebson
Final Report (November 2004)
A detailed genotype-phenotype correlation study in Rett syndrome
This study aimed to examine associations between the type and position of mutations in the MECP2 gene and clinical characteristics in a large cohort of patients from the UK with Rett syndrome, specifically attempting to recruit a large number of 'atypical' cases who may be most informative in terms of establishing such associations. We adopted a novel approach to dissecting genotype-phenotype relationships (focusing on just 3 main aspects, or 'dimensions', of the phenotype - the 'typicality' of the disorder, the severity and the age-of-onset) and to subdividing groups of mutations (missense, early truncating and late truncating groupings only). Effects of individual mutations on phenotype were also examined, as was the effect of X chromosome inactivation (XCI) ratio.
We recruited 191 families to the study. This included 140 cases with classic Rett syndrome and 51 cases with atypical Rett syndrome. 135 cases had identified mutations in MECP2.
The main findings were that cases with early onset of regression and seizures, and those with clinical features that might indicate alternative causes of the disorder, were more likely to have no identified 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. It was confirmed that different common individual mutations were associated with more severe and less severe presentations. There was evidence suggesting that the X-inactivation ratio (XCI) moderated the effect of genotype on phenotype.
In summary, the approach we used allowed us to identify novel genotype-phenotype associations that may aid our understanding of the pathogenesis of Rett syndrome and also contribute to clinical knowledge.
We hope that information from this study will help both families and doctors of Rett syndrome patients around the world in their understanding of how the degree of severity of the disorder is related to the underlying genetic cause in individual patients.