Background Rett syndrome is a genetically caused neurodevelopmental disorder associated with functional deficits and comorbidities. This study investigated relationships between genotype, functional abilities and comorbidities and quality of life in Rett syndrome.

Methods The International Rett Syndrome Database, InterRett, was used as a sampling frame for this observational study. Information was collected to describe functional abilities (walking and feeding), health (Sleep Disorder Scale for Children, the Rett Syndrome Behavioural Questionnaire), parental health (12-item Short Form Health Survey) sociodemographic factors (parental employment and education) and quality of life (Quality of Life Inventory-Disability) for 210 individuals with Rett syndrome. Univariate and multivariate regressions were used to analyse the relationships between the independent variables and quality of life.

Results Compared with individuals with the p.Arg270* mutation, those with the p.Arg294* mutation type had the poorest quality of life (coeff −12.81, 95% CI –23.49 to 2.12), despite this being recognised as a clinically milder genotype. Overall better walking and feeding skills and seizure parameters were more associated with better quality of life and poor sleep and behavioural difficulties with poorer quality of life.

Conclusions These findings suggest that genotype, functioning and health each have implications for quality of life and should be considered when counselling families and planning clinical and support management strategies.