Submission Details

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), the ID/Autism Gene Curation Expert Panel 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 (PMID: 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. The gene-disease relationship is supported by experimental evidence of functional alteration in patient fibroblast cells which support impaired histone acetylation (PMID: 22265017), and protein interactions with other autosomal dominant intellectual disability genes, such as BRPF1 (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 classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 4, 2023 (SOP version 9).