Intellectual disabilityGene: KAT5 Red List (low evidence)
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
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.