Spectrum of MECP2 mutations in Indian females with Rett Syndrome - a large cohort study

Aim: This study aimed to characterize MECP2 gene variants in Indian female patients with classical Rett syndrome (RTT). Methods: Seventy-two patients fulfilling the revised diagnostic criteria of classical RTT were enrolled and exons 2-4 of MECP2 gene were analyzed by Sanger sequencing followed by quantitative analysis using MLPA. Bioinformatic analysis was done using different software packages to predict the effect of sequence variations on the function of the MeCP2 protein. Results: A heterogeneous spectrum of MECP2 sequence variants including 13 novel variants was identified with a detection rate of 98.6%. The majority of the variants were distributed in the functional domain of MECP2 with most missense variants clustered in methyl binding domain and truncating variants in interdomain and transcription repression domain of MECP2 . Genotype-phenotype correlations revealed that patients carrying early truncating variants presented with a more severe phenotype. Conclusion: RTT is a childhood neurodevelopmental disorder primarily affecting females. It is caused by mutations in the Methyl-CpG-Binding Protein 2 gene (MECP2), an important regulator of gene expression, located at Xq28. Variants in MECP2 can be identified in 95%-97% of individuals with Classical RTT using a combination of molecular techniques. This large cohort study from India showed the highest detection rate of MECP2 variants in classical RTT patients, emphasizing the importance of using diagnostic criteria and having a multidisciplinary team in the assessment of RTT patients, which can further help provide diagnostic testing, genetic counseling, and prenatal testing