Genotype-Phenotype Correlation and Therapeutic Amenability in a Cohort of Rett Syndrome Patients: A Single-Center...

Introduction Classical Rett syndrome (RTT) is a rare progressive neurodevelopmental disorder associated with mutations in the MECP2 gene. This study aims to correlate the genetic mutations and phenotype characteristics of a cohort of RTT syndrome patients and evaluate their amenability to novel therapies, including Trofinetide. Methods We conducted a retrospective observational review of a case series (2000-2024) of RTT patients at Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates (ARE). We included patients under 16 years of age with classic RTT and a confirmed MECP2 mutation. We analyzed demographic, clinical, and genetic data to determine genotype-phenotype correlations. Results Of 13 patients with RTT syndrome, 8 patients had genetic data on record and were included in the phenotype-genotype correlation analysis; the entire cohort (n=13) was included in the clinical profiling. The age at presentation was 11.2 years, and the median age was 23 months. The distribution of patients' stages at presentation was as follows: 7(53%) were in stage I, 5 (38%) were in stage II, and 1 (8%) were in stage III. Progression to Stages III and IV took place collectively in 9 (75%) of patients. Of the eight patients with genetic data, 6/8 (75%) had variants classified as pathogenic/likely pathogenic, whereas 2/8 (25%) had variants classified as variants of unknown significance (VUS) or benign, however, both met clinical diagnostic criteria for RTT and were assessed by the authors and treating team as pathogenic. These two novel variants were in two classical patients with RTT, classified as VUS (1330G>A) and benign (641C>A). The cohort revealed a high frequency of comorbidities, including epilepsy 8 (61%), behavioral disturbances 7 (53%), gastrointestinal complications 6 (46%), and scoliosis 4 (30%). 5 (43%) of patients had MRI abnormalities. As for treatment amenability, all patients in our cohort are eligible for the only currently approved treatment (Trofinetide), regardless of genotype-phenotype correlation. Conclusion This study demonstrates the clinical and genetic heterogeneity in RTT, and the value of genotyping for confirmation, assessment, and management planning. While no genotype-phenotype profile excludes treatment eligibility with Trofinetide, this correlation may inform early life response to treatment and eligibility for other emerging therapeutic options such as gene therapy. Early recognition, diagnosis, and treatment will certainly have an impact on patient outcomes.