Genomic insights into Rett syndrome-like features in Bangladeshi participants.

PURPOSE: Rett syndrome (RTT) is a neurological disorder marked by the loss of developmental milestones. Classic RTT involves variants in the methyl-CpG-binding protein 2 (MECP2) gene. Our study examines the genetic basis of typical and atypical RTT, along with RTT-like phenotypes, using MECP2-targeted sequencing (TS) and exome sequencing (ES).

METHODS

MECP2 sequencing was conducted on 27 Bangladeshi female participants with RTT features. ES was subsequently conducted on the 13 participants who tested negative for MECP2 variants. Data were processed using the Genome Analysis Toolkit and American College of Medical Genetics and Genomics-guided pathogenicity analysis was conducted with ANNOVAR and GenomeArc Horizon. Copy-number variation analysis was performed using CNVkit, and variants were classified according to the American College of Medical Genetics and Genomics guidelines.

RESULTS

Of the 27 participants, 51.9% (14/27) had pathogenic MECP2 variants, all exhibiting the classic RTT phenotype, yielding an 87.5% (14/16) diagnostic rate for classic RTT through TS. The identified variants included 3 missense, 3 nonsense, and 3 frameshift deletions. Among the 13 MECP2-negative participants who underwent ES, 69.2% (9/13) harbored pathogenic variants, whereas 23.1% (3/13) carried a variant of uncertain significance, and 7.7% (1/13) had no clinically relevant variants. ES analysis identified 6 candidate genes were associated with atypical RTT (CACNA1E) and RTT-like phenotypes (ARHGEF9, KMT2C, TBC1D23, PGAP3, and LEO1). The overall diagnostic yield for TS and ES was 85.2% (23/27).

CONCLUSION

This genetic study of clinically diagnosed Bangladeshi RTT participants identifies new genes involved in the etiology of RTT-like phenotypes and expands the phenotypic spectrum of known genes linked to neurodevelopmental disorders.