Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

KAT6B : RASopathy

HGNC:17582 | MONDO_0021060
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: RASopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
Kraft M et al. 2011 Sep (PMID:21804188);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 0.5 0.5
Kraft M et al. 2011 Sep (PMID:21804188);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 1.5 1.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Cannot score only human variant as it is a multigenic translocation.
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).