Expanding the genetic landscape of Rett syndrome to include lysine acetyltransferase 6A (KAT6A) (Letter)

Abstract

Pathogenic variants in methyl-CpG protein 2 (MECP2; OMIM 300005) result in an X-linked, severe, and progressive epigenetic disorder, Rett syndrome (RTT, OMIM: 312750), that predominantly affects females (Rett, 1966). Using Neul's revised diagnostic criteria, affected individuals can be clinically classified as classic or atypical RTT (Neul et al., 2010). After 6–18 months of apparently normal development, girls with the classic form of RTT gradually start losing their previously acquired skills including spoken language and other communication, coordination, and social interaction. Along with acquired microcephaly, affected girls lose purposeful use of their hands and develop midline stereotypic hand movements, breathing irregularities, seizures, scoliosis, and disturbed sleeping patterns. The partial/complete loss of spoken language is one of the core diagnostic criteria which is essential to be present for an affected individual to be classified as an individual with classic RTT. However, it is not necessarily a required criterion when classifying individuals with atypical RTT (Neul et al., 2010; Schonewolf-Greulich et al., 2019). As per the definitions adopted in the article by Neul et al. (2010) “… an individual who had learned to babble but then loses this ability is considered to have a loss of acquired language …” Owing to the broad variability of the phenotype in individuals with RTT, a proportion of them satisfy some, but not all, of the necessary revised diagnostic criteria and are classified as atypical RTT. Furthermore, individuals may be classified as RTT-like, exhibiting some clinical features associated with RTT, but not enough to be classified as either classic or atypical RTT (Ip et al., 2018). Approximately 97% of individuals with classic RTT and 86% of individuals with atypical RTT have pathogenic variants in MECP2 (Neul et al., 2014). A small proportion of individuals with clinical features overlapping with RTT have been reported with pathogenic variants in cyclin-dependent kinase-like 5 (CDKL5, OMIM: 300203) and forkhead box G1 (FOXG1, OMIM: 164874); however, a significant proportion of individuals clinically classified as RTT remain without a definite genetic diagnosis (Armani et al., 2012).