Submission Details

KAT6A was first reported in relation to autosomal dominant syndromic intellectual disability in 2015 on six individuals from five unrelated families (Tham et al., PMID: 25728777). KAT6A encodes for an acetyltransferase that is a member of the MYST family of proteins, which acetylates lysine-9 residues in histone 3, regulating transcriptional activity and gene expression. Patients with KAT6A pathogenic variants present intellectual disability, speech delay, microcephaly, cardiac anomalies and gastrointestinal complications (reflux, feeding difficulty,intestinal malrotation) with variable expressivity. KAT6A variants have been noted to be associated with the following disease entities: Arboleda-Tham syndrome(616268), KAT6A syndrome, dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (ORPHA:457193), syndromic developmental delay as found in OMIM, MonDO, Orphanet and the literature. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern and phenotypic variability. Therefore, these disease phenotypes have been lumped into one disease entity. Ten variants (8 loss-of-function and 2 missense) that have been reported in 14 probands in 4 publications (PMIDs: 25728775,32041641, 29899504, 27133397) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. More than 50 variants are reported, most of which are de novo truncating in the ultimate and penultimate exons of the gene. Literature suggests that truncated protein products may have a more severe consequence than heterozygous loss-of-function, which would suggest that truncations in the ultimate or penultimate exon could have a dominant negative effect or neomorphic effects.Six missense variants have been reported at highly conserved regions of the protein and require further functional studies to definitively confirm pathogenicity. There is limited experimental evidence including two mouse models (PMIDs: 27133397, 22921202) and a rescue (PMID: 19922872); however, the scores for one of the mouse models (PMID: 22921202) and the rescue have been downgraded to 0 points because the phenotypes reported are not associated with a neurodevelopmental phenotype. In summary, there is definitive evidence to support the relationship between KAT6A and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.