Intellectual disabilityGene: KAT8
Added 'missense' tag because all de novo variants in PMID:31794431 are missense. Note that for the biallelic case in the same paper, one of the variants is nonsense.
Created: 1 Jun 2020, 3:41 p.m. | Last Modified: 1 Jun 2020, 3:41 p.m.
Panel Version: 3.76
Comment on mode of inheritance: Individual T9 inherited biallelc variants from her asymptomatic parents. Her sister carried 1 variant and showed no obvious symptoms. This may be due to incomplete genetic penetrance, or the two variants act differently from the de novo heterozygous variants identified. This is the only example of biallelic inheritance, so have set MOI to 'monoallelic' until more cases are identified.
Created: 1 Jun 2020, 3:39 p.m. | Last Modified: 1 Jun 2020, 3:39 p.m.
Panel Version: 3.75
Comment on list classification: Gene was added to the panel and rated Green by Konstantinos Varvagiannis, and subsequently reviewed Green by Zornitza Stark. Not yet associated with a disorder in OMIM or G2P. All cases come from PMID:31794431 (Li et al.2019) who report 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants (T1,T2,T3 had the same variant), plus one individual compound het for a nonsense and a missense variant (p.Lys175* and p.Arg325Cys). All individuals had DD and/or ID (Supplementary materials). Knockout mice failed to thrive, and showed early lethality and cerebral hypoplasia.
Created: 1 Jun 2020, 3:36 p.m. | Last Modified: 1 Jun 2020, 3:36 p.m.
Panel Version: 3.74
Eight unrelated individuals reported with de novo variants in this gene and a mouse model. All variants missense, in the chromobarrel domain or the acetyltransferase domain; three individuals had the same variant p.Tyr90Cys . One more individual reported with bi-allelic variants: one missense and one frameshift; carrier parents were normal suggesting that may be haploinsuffiency is not the mechanism.
Created: 8 Feb 2020, 8:53 a.m. | Last Modified: 8 Feb 2020, 8:53 a.m.
Panel Version: 3.0
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability; seizures; autism; dysmorphic features
Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below].
Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one.
Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1).
The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected.
All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal.
KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5.
KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders.
Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif.
FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation.
The nonsense variant demonstrated abnormal subnuclear localization.
The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model.
Created: 15 Dec 2019, 9:28 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism
Tag missense tag was added to gene: KAT8.
Mode of pathogenicity for gene: KAT8 was changed from None to Other
Mode of inheritance for gene: KAT8 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: kat8 has been classified as Green List (High Evidence).
gene: KAT8 was added gene: KAT8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism Penetrance for gene: KAT8 were set to unknown Review for gene: KAT8 was set to GREEN