KAT6B

Inheritance Pattern: AD

Disease ID:MONDO:0036042

Submitter: ClinGen

Variants in *KAT6B* have been reported in individuals with clinical diagnoses of both Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GPS). SBBYSS is a multiple anomaly syndrome characterized by blepharophimosis and a mask-like facial appearance (PMID: 22077973). GPS is a rare skeletal dysplasia combining hypoplastic or absent patellae, genital anomalies, craniofacial defects, and intellectual disability among other features (PMID: 22265014). Both phenotypes are characterized by some degree of global developmental delay, intellectual disability, hypotonia, genital abnormalities, and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs (PMID: 23236640). In more recent literature, SBBYSS and GPS are considered subtypes of *KAT6B*-related disorders, which also include individuals with intermediate phenotypes consisting of SBBYSS and GPS features. Additionally, both phenotypes are most often caused by truncating variants in the last exon (exon 18) of the gene (PMID: 32424177). Per criteria outlined by the ClinGen Lumping and Splitting Working Group and a published review (PMID: 28857140), we decided to lump these phenotypes into one disease entity known as *KAT6B*-related multiple congenital anomalies syndrome. To date, over 100 individuals with *KAT6B*-related disorders have been reported (PMIDs: 25424711, 32424177, 34519438). Inheritance in most cases is *de novo*. Most SBBYSS-causing variants are located in the distal part of exon 18 or more proximally placed in exons 13-17, while GPS pathogenic variants are located in the more distal part of exon 17 and in the proximal region of exon 18 (PMID: 34519438). The mechanism of pathogenicity is not well elucidated. While nonsense-mediated decay is not anticipated for variants in the last exon (PMID: 22265014), more proximal variants have typically been associated with a milder presentation of SBBYSS and are thought to lead to nonsense-mediated decay and haploinsufficiency (PMID: 2542471). Variants that affect critical domains in the C-terminal region and result in expression of a truncated protein product may lead to GPS or SBBYSS (PMIDs: 25424711, 32424177). Nine null variants in exon 18 (three associated with SBBYSS, three with GPS and three with intermediate phenotypes) are included in this curation (PMIDs: 22077973, 22265014, 25424711, 32424177). *KAT6B* encodes a histone acetyltransferase. This gene-disease relationship is also supported by experimental evidence showing impaired histone acetylation in patient fibroblasts (PMID: 22265017), and protein interactions with BRPF1, involved in autosomal dominant syndromic intellectual disability (PMID: 18794358). Furthermore, *Kat6b* knockout mouse models show defects in brain development and adult neurogenesis, craniofacial defects and digital anomalies (PMID: 10821753, 17079664, 22077973, 30790630). In summary, there is definitive evidence to support the relationship between *KAT6B* and autosomal dominant *KAT6B*-related multiple congenital anomalies 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 Intellectual Disability and Autism Gene Curation Expert Panel and by the ClinGen Congenital Anomalies of the Kidney and Urinary Tract Gene Curation Expert Panel (secondary contributor) on January 4, 2023 (SOP version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0011640

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011365

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011640

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011365

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0011365

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011640

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0036042

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0021060

Submitter: ClinGen

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).