Rett syndrome and kat6a-related disorders: Chromatinopathies with overlapping clinical trajectories

Abstract

Background: Chromatin regulation is one of the most notable pathways affected in neurodevelopmental disorders (NDDs) including Rett syndrome (RTT), a pediatric-onset progressive neurological condition. Individuals with some but not enough diagnostic criteria are often referred to as RTT-like. Although RTT is mainly caused by pathogenic variants in the X-linked transcriptional regulator Methyl-CpG-binding protein 2 (MECP2) gene, up to 13% of RTT individuals are genetically undiagnosed. Aim: We aimed to use the combination of next-generation sequencing (NGS) in a cohort of genetically undiagnosed RTT/RTT-like individuals to better understand the genetic and clinical spectrum of RTT and related NDDs. Methods: Using NGS, we have identified five RTT/RTT-like individuals with pathogenic variants in KAT6A. We then undertook a thorough systematic re-assessment of 76 previously published individuals with KAT6A-related disorder (Kennedy et al., 2019), which led to the re-classification of an additional two patients as RTT/RTTlike according to the Neul diagnostic criteria for RTT. Results: We report seven individuals with pathogenic variants in KAT6A who have overlapping clinical features with RTT and KAT6A-related disorders. All de novo heterozygous, late truncating variants were clustered in exon 17 of KAT6A and resulted in loss of the well-conserved C-terminal domain critical for binding of transcriptional co-regulators for regulation of target genes expression. Conclusion: Although variants in KAT6A have been previously associated with KAT6Arelated disorders, the association with RTT appears to have been previously unrecognized. This is the first report linking RTT/RTT-like clinical phenotypes with pathogenic variants in KAT6A, expanding the overlapping landscape of NDDs.L6371736222022-02-10 <br />