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Intellectual disability

Gene: KAT5

Red List (low evidence)

KAT5 (lysine acetyltransferase 5)
EnsemblGeneIds (GRCh38): ENSG00000172977
EnsemblGeneIds (GRCh37): ENSG00000172977
OMIM: 601409, Gene2Phenotype
KAT5 is in 3 panels

1 review

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Humbert el al (2020 - PMID: 32822602) report 3 individuals with de novo missense KAT5 variants.

Features included severe DD (3/3) and ID (2/2 - the 3rd was 18m on last examination), microcephaly (2/3), behavioral anomalies (3/3) including severe sleep disorder (3/3 - table S1 / night walking, sleep onset delay, excessive daytime sleepiness), seizures (3/3 - variable type and age of onset), brain MRI abnormalities (3/3 - CC, cerebellar atrophy each in 2 subjects, focal polymicrogyria in 1), various genitourinary anomalies (3/3). All had moderately short stature (-1.95 SD to -2.9SD). Cleft LP and submucous cleft P were observed in 2/3. Facial features included round face, flat profile, depressed nasal bridge, downturned corners of mouth and prognathism (each in at least 2 subjects).

KAT5 encodes a lysine acetyltransferase involved in gene expression, DNA repair, chromatine remodeling, apoptosis and cell proliferation. It is part of the NuA4 histone acetyltransferase (HAT) complex also called TIP60/p400 (TIP60 being another name for KAT5). Regulation by histone acetylation is important for proper development.

3 missense KAT5 SNVs were identified, one within the chromobarrel domain (aa 7-65 / NM_006388.3) and 2 in the acetyl-CoA binding domain (aa 365-420).

Following generation of K562 cells expressing either WT or variants, it was demonstrated that wt/mt KAT5 assemble normally into NuA4/TIP60 complexes. Histone acetyltransferase activity was however impaired for all variants, suggesting a partial loss of function mechanism.

As Humbert et al comment, it is possible that KAT5 haploinsufficiency does not lead to a
syndrome. Over 10 high-confidence LoF variants are listed in gnomAD. Heterozygous Kat5 ko mice have normal development, growth and fertility. Homozygous ko mice are embryonic lethal. In haploinsufficient mice, reduction of mRNA to 50% has been shown to be compensated at the protein level in adipose and/or other tissues (several studies cited).

RNA-Seq in fibroblasts from 2 affected individuals revealed dysregulation of highly relevant genes (e.g. for neurodevelopment, circadian clock, etc).

Mutations in KAT6A/B, encoding two other acetyltransferases cause neurodevelopmental disorders with features overlapping those observed in individuals with KAT5 variants (e.g. DD/ID, microcephaly, seizures, sleep disturbance, clefts, CC or genital anomalies).

Consider inclusion in the ID and epilepsy panels with green rating as well as the gene panel for clefting with amber.
Created: 22 Aug 2020, 9:49 p.m. | Last Modified: 22 Aug 2020, 9:49 p.m.
Panel Version: 3.262

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Severe global developmental delay; Intellectual disability; Seizures; Microcephaly; Behavioral abnormality; Sleep disturbance; Morphological abnormality of the central nervous system; Short stature; Oral cleft; Abnormality of the face


Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments


Clinvar variants
Variants in KAT5
Panels with this gene

History Filter Activity

28 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: KAT5 was added gene: KAT5 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: KAT5 was set to