Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

Background: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (). Our objective to investigate the genetic landscape of -negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES).

Methods: We performed WES on 77 -negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria.

Results: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including ) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H transporting V0 subunit A1 (), ubiquitin-specific peptidase 8 () and microtubule-associated serine/threonine kinase 3 (), as well as biallelic variants in nuclear receptor corepressor 2 ().

Conclusions: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.