Submission Details

KAT6B was first reported in relation to autosomal dominant Genetic multiple congenital anomalies/dysmorphic syndrome in 2011 (Clayton-Smith et al., PMID: 22077973). The KAT6B gene is located on chromosome 10 at 10q22.2 and encodes the Lysine acetyltransferase 6B. KAT6B codes for histone acetyltransferase and component of the MOZ/MORF protein complex and functions to regulate genes important for early development, including the development of the skeleton and nervous system. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern, with minimal difference in phenotypic variability. Therefore, the following disease entities, Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) and Genitopatellar Syndrome (GPS), have been lumped into one disease entity, Genetic multiple congenital anomalies/dysmorphic syndrome. 15 variants (nonsense, frameshift, small deletion/insertions) that have been reported in 18 probands in 4 publications (PMIDs: 22265014, 22077973, 29899993, 23436491) are included in this curation. The majority of variants occur in sporadic cases de novo and are predicted to result in premature termination and loss of the highly conserved transcription activation domain. 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 LOF. This gene-disease association is also supported by animal models, expression studies, and functional alteration studies. (PMIDs: 22265017, 22265014, 22077973). Mice carrying a gene trap insertion in the mouse ortholog Kat6b mutant displayed a number of defects that reflected SBBYSS syndrome with a milder phenotype. Additionally, immunohistochemistry on mice of various developmental ages demonstrated the expression of the murine KAT6B homolog, Myst4. Finally, the truncated form of KAT6B expressed in skin fibroblast from patient cells were demonstrated to have significant reductions in H3 and H4 acetylation. In summary, KAT6B is definitively associated with autosomal dominant Genetic multiple congenital anomalies/dysmorphic syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen CAKUT GCEP on the meeting date 08/08/22 (SOP Version 9).