The most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome

Abstract Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that is caused by mutations in the MECP2 gene; however, defects in other genes ( CDKL5 and FOXG1 ) can lead to presentations that resemble classic RTT, although they are not completely identical. Here, we attempted to identify other monogenic disorders that share features of RTT. A total of 437 patients with a clinical diagnosis of RTT-like were studied; in 242 patients, a custom panel with 17 genes related to an RTT-like phenotype was run via a HaloPlex-Target-Enrichment-System. In the remaining 195 patients, a commercial TruSight-One-Sequencing-Panel was analysed. A total of 40 patients with clinical features of RTT had variants which affect gene function in six genes associated with other monogenic disorders. Twelve patients had variants in STXBP1 , nine in TCF4 , six in SCN2A , five in KCNQ2 , four in MEF2C and four in SYNGAP1 . Genetic studies using next generation sequencing (NGS) allowed us to study a larger number of genes associated with RTT-like simultaneously, providing a genetic diagnosis for a wider group of patients. These new findings provide the clinician with more information and clues that could help in the prevention of future symptoms or in pharmacologic therapy.