Co-Occurring Genetic Mutations in Rett Syndrome and MECP2-Related Disorders-Clinical and Diagnostic Implications from a Case Series.

Background/Objectives: Factors modulating phenotypic variability in Rett syndrome (RTT, OMIM 312750) include X chromosome inactivation (XCI), type of MECP2 variant, and/or disease modifiers. Emerging evidence also points to multi-locus genetic variants. Understanding the phenotypic variability associated with multi-locus genetic diagnoses in individuals with RTT and MECP2-related disorders would be important not only for accurate diagnosis, risk stratification and clinical management but also to explain symptoms that might not be typically associated with RTT. Methods: We present a case series of five individuals with a diagnosis of RTT or an MECP2-related disorder with co-occurring genetic findings, including pathogenic variants, variants of unknown significance and chromosome duplications. Clinical features such as neurodevelopmental history and comorbid medical conditions were assessed alongside the genetic findings. Results: A review of 200 cases with RTT identified five cases (all females aged 7-27 years) with a co-occurring genetic finding. Each case harboured at least one additional genetic variant that included a beta thalassaemia trait, Calmodulin 3 (CALM3) missense variant, maternally inherited 22q12.3 to q13.1 duplication, 7p14.3 and Dynein Cytoplasmic 1 Heavy Chain 1 (DYNC1H1) variants of uncertain significance and a pathogenic Set Domain-containing protein 5 (SETD5) variant. A rare triple genetic finding was illustrated in a single case, combining MECP2, CALM3, and DYNC1H1 variants. Conclusions: This case series supports the premise that RTT and MECP2-related disorders exist in a more complex neurogenetic spectrum than previously defined. It also emphasises the complexity within MECP2-related disorders. They are not static, and in the context of severe treatment resistant epilepsy, MECP2 disorders can evolve over time, necessitating diagnostic reclassification. Although the co-occurrence of multiple genetic disorders in RTT and MECP2-related disorders is rare, these cases underscore the importance of considering cumulative genetic burden when evaluating individuals with atypical features or evolving neurodevelopmental phenotypes.