Submission Details

KAT6B was first reported in relation to autosomal dominant RASopathies in 2011 (Kraft et al., PMID 21804188). However, only 1 variant (complex rearrangement) has been reported to be associated with a “Noonan-like phenotype” in humans. While evidence supporting this gene-disease relationship includes case-level data and experimental data, variants in this gene have been reported in at least 1 proband in 1 publication (Kraft et al. 2011 PMID 21804188). Additionally, the variant identified in the patient described to have a Noonan-like phenotype was a balanced translocation t(10;13)(q22.3;q34) disrupting the gene. Of note, truncating mutations in this gene have also been implicated in Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome. These relationships will be assessed separately. The association with RASopathies is supported by a mouse model demonstrating craniofacial and growth abnormalities consistent with RASopathies as well as functional alteration studies in patient cells demonstrating changes in RAS MAPK signaling. However, the mouse model is lacking specificity for RASopathies and cannot be distinguished from SBBYSS, as the same transgenic mice have independently been reported to model SBBYSS (PMID 22077973). Moreover, the RASopathy expert panel believes that the diagnosis of the reported translocation patient (Kraft et al., 2011 PMID 21804188) is more compatible with (mild) SBBYSS than Noonan syndrome. This patient was also described to have SBBYSS in another publication disputing the Noonan-like association (Clayton-Smith et al. 2011 PMID 22077973). The alterations of RAS/MAPK signaling observed in a lymphoblastoid cell line from this patient might be a hint that altered RAS/MAPK signaling contributes to the complex pathophysiology related to KAT6B-mediated chromatin modulation, but the reported data seem to be insufficient to account the disease solely to a dysregulation of this pathway. The possible relationship between KAT6B and RAS/MAPK pathway regulation needs further investigation. In summary, the evidence supporting the relationship between KAT6B and AD RASopathies is Disputed as no human genetic evidence can be scored. Neither the phenotype nor the nature of the genetic change support differentiation from SBBYSS. More evidence is needed to either support or refute the role KAT6B plays in this disease. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 2/4/2019 (SOP Version 5).