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

<b>Background/Objectives</b>: Factors modulating phenotypic variability in Rett syndrome (RTT, OMIM 312750) include X chromosome inactivation (XCI), type of <i>MECP2</i> 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 <i>MECP2</i>-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. <b>Methods</b>: We present a case series of five individuals with a diagnosis of RTT or an <i>MECP2</i>-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. <b>Results</b>: 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, <i>Calmodulin 3</i> (<i>CALM3</i>) missense variant, maternally inherited 22q12.3 to q13.1 duplication, 7p14.3 and <i>Dynein Cytoplasmic 1 Heavy Chain 1</i> (<i>DYNC1H1</i>) variants of uncertain significance and a pathogenic <i>Set Domain-containing protein 5</i> (<i>SETD5</i>) variant. A rare triple genetic finding was illustrated in a single case, combining <i>MECP2</i>, <i>CALM3</i>, and <i>DYNC1H1</i> variants. <b>Conclusions:</b> This case series supports the premise that RTT and <i>MECP2</i>-related disorders exist in a more complex neurogenetic spectrum than previously defined. It also emphasises the complexity within <i>MECP2</i>-related disorders. They are not static, and in the context of severe treatment resistant epilepsy, <i>MECP2</i> disorders can evolve over time, necessitating diagnostic reclassification. Although the co-occurrence of multiple genetic disorders in RTT and <i>MECP2</i>-related disorders is rare, these cases underscore the importance of considering cumulative genetic burden when evaluating individuals with atypical features or evolving neurodevelopmental phenotypes.