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

Area of Science:

• Neurogenetics
• Clinical Genetics

Background:

• Rett syndrome (RTT) and MECP2-related disorders exhibit phenotypic variability influenced by X chromosome inactivation, MECP2 variant type, and disease modifiers.
• Emerging evidence suggests multi-locus genetic variants contribute to this variability.
• Understanding complex genetic diagnoses is vital for accurate RTT diagnosis, risk stratification, and explaining atypical symptoms.

Purpose of the Study:

• To investigate the impact of co-occurring genetic findings on the phenotype of individuals with RTT or MECP2-related disorders.
• To highlight the importance of considering cumulative genetic burden in complex neurodevelopmental cases.

Main Methods:

• Case series analysis of five individuals with RTT or MECP2-related disorders and additional genetic findings.
• Assessment of clinical features, neurodevelopmental history, and comorbid conditions alongside genetic data.
• Review of 200 RTT cases to identify individuals with co-occurring genetic diagnoses.

Main Results:

• Five female cases (aged 7-27) with RTT or MECP2-related disorders and co-occurring genetic findings were identified.
• Identified co-occurring variants included beta thalassaemia trait, CALM3 missense variant, 22q12.3-q13.1 duplication, DYNC1H1 variants of uncertain significance, and a pathogenic SETD5 variant.
• One case presented a rare triple genetic finding involving MECP2, CALM3, and DYNC1H1 variants.

Conclusions:

• RTT and MECP2-related disorders represent a more complex neurogenetic spectrum than previously understood.
• MECP2 disorders can evolve, especially with treatment-resistant epilepsy, necessitating diagnostic reclassification.
• Co-occurrence of multiple genetic disorders, though rare, underscores the need to consider cumulative genetic burden in atypical or evolving neurodevelopmental phenotypes.