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Published on: May 22, 2019
p.R270X MECP2 mutation and mortality in Rett syndrome
Le Jian1, Hayley L Archer, David Ravine
1Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
Abstract:
Among cases in the Australian Rett Syndrome Database, the nonsense mutation p.R270X is one of the most commonly occurring single pathogenic MECP2 mutations. In two recent published reports of the MECP2 mutational spectrum the p.R270X appeared to be under represented. We hypothesised that increased mortality arising from this mutation may underlie this apparent discrepancy. We investigated our hypothesis in two independent study groups from Australia and the UK with prospective data collections (total n=524). Only females with Rett syndrome and an identified MECP2 mutation were included. Significant differences in survival were detected among Rett syndrome cases grouped for the eight most frequent mutations (log-rank chi(2) (7)=15.71, P=0.03). Moreover, survival among cases with p.R270X, when compared with survival among cases with all the other mutations was reduced (log-rank chi(2) (2)=6.94, P=0.01). Our observation of a reduced survival associated with the p.R270X mutation offers an explanation for the under representation of p.R270X in older subjects with Rett syndrome.
Insights
The common p.R270X mutation in MECP2 causes Rett syndrome and is linked to increased mortality. This finding explains why this specific mutation is underrepresented in older Rett syndrome patients.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- The MECP2 gene is crucial for neurodevelopment, and mutations cause Rett syndrome.
- The p.R270X nonsense mutation is a frequent MECP2 mutation, yet appears underrepresented in some studies.
- This underrepresentation may suggest increased mortality associated with the p.R270X mutation.
Purpose of the Study:
- To investigate the hypothesis that increased mortality is associated with the p.R270X MECP2 mutation in Rett syndrome.
- To determine if the p.R270X mutation impacts survival rates compared to other MECP2 mutations.
Main Methods:
- Analysis of two independent prospective cohorts from Australia and the UK, totaling 524 female patients with Rett syndrome and identified MECP2 mutations.
- Survival analysis using log-rank tests to compare survival rates among different MECP2 mutation groups, specifically comparing p.R270X to all other mutations.
Main Results:
- Significant differences in survival were observed among Rett syndrome cases grouped by their eight most frequent MECP2 mutations (P=0.03).
- Survival was significantly reduced in cases with the p.R270X mutation compared to all other MECP2 mutations (P=0.01).
Conclusions:
- Reduced survival associated with the p.R270X mutation provides a likely explanation for its underrepresentation in older individuals with Rett syndrome.
- This study highlights the importance of considering mutation-specific mortality rates in understanding the clinical spectrum of Rett syndrome.
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