A novel heterozygous pathogenic variation in the MECP2 gene causing typical Rett syndrome: a case report

Rett syndrome (RTT) is an X-linked neurodevelopmental disease with clear diagnostic criteria and mainly affects females. Mutations of the methyl-CpG-binding protein 2 (MECP2) gene cause most RTT cases. While numerous MECP2 mutations have been reported, the pathogenicity of novel identified variants often requires functional validation. To obtain a definite genetic diagnosis result and determine the specific pathogenesis, it is essential to conduct functional validation of the novel mutation.

We reported one clinical case of a female child diagnosed with typical RTT. The patient presented with major clinical manifestations, including hand dyspraxia, loss of language ability, stereotypical hand movements, and an abnormal gait. Whole-exome sequencing (WES) was performed on this Chinese trio, which confirmed a novel heterozygous nonsense mutation in exon 1 of the MECP2 gene in the proband. Sanger sequencing confirmed that neither parent carried this variant. Functional validation experiments demonstrated that cells transfected with the mutant recombinant plasmid showed significantly reduced levels of both MECP2 messenger RNA (mRNA) and protein compared to those transfected with the wild-type plasmid.

These functional findings confirm the pathogenicity of this de novo MECP2 nonsense mutation and demonstrate that it leads to a loss of function, a mechanism consistent with nonsense-mediated mRNA decay (NMD). Our study elucidates the genotype-phenotype correlation in this case and provides experimental insight into the underlying molecular mechanism.