GPS and SBBYSS are hypothed to occur through a Gain-of-Function and Loss-of-Function disease mechanism, respectively. Pathogenic variants, which include nonsense, missense, splice site, and predicted frameshift variants, are most often located in exon 18, the last exon of the gene.
Most pathogenic variants causing GPS cluster in KAT6B exon 18 and are predicted to escape nonsense-mediated decay, resulting in a truncated protein causing disease via a suspected gain-of-function/dominant negative mechanism hypothed to occur from altered binding affinity or dysregulated interactions of KAT6B with its natural binding partners. This has not yet been tested experimentally. SBBYSS-causing pathogenic variants occur throughout the gene are hypothed to be Loss-of-Function variants. SBBYSS-associated variants occur most frequently in exon 18, but more distally than the GPS-associated variants. More proximal disease-associated variants in exons 3, 7, 11, and 14-17 have also been reported. The SBBYSS phenotype is hypothed to result from the loss of KAT6B functions.
KAT6B