Early onset or syndromic epilepsy

Gene: KAT5

Green List (high evidence)

Agree to rate as green and monoallelic inheritance.

Created: 27 Apr 2022, 9:13 a.m. | Last Modified: 27 Apr 2022, 9:13 a.m.

Panel Version: 2.518

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder with dysmorphic facies, sleep disturbance and brain abnormalities

Publications

• 32822602

Comment on list classification: Rating upgraded from Red to Amber. There is a sufficient number of unrelated cases reported in PMID:32822602 to promoted this gene to Green at the next GMS panel update.

Created: 9 Oct 2020, 3:20 p.m. | Last Modified: 9 Oct 2020, 3:20 p.m.

Panel Version: 2.167

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, 9:48 p.m. | Last Modified: 22 Aug 2020, 9:48 p.m.

Panel Version: 2.143

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

Phenotypes
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

Publications

• 32822602

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

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Red.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Red List (low evidence)

No link on OMIM to epilepsy syndrome.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
Unknown

Phenotypes
Smith-Magenis-like syndrome; schizophrenia

Publications

• 28213671
• 28195569

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Comment on list classification: Based on expert reviewers' comments.

Created: 6 Dec 2018, 2:52 p.m.

Red List (low evidence)

I cannot find any publications linking this gene with disease.

Created: 16 Aug 2018, 1:12 a.m.