Activity

Filter

Cancel
Date Panel Item Activity
22 actions
Early onset or syndromic epilepsy v2.518 KAT5 Helen Lord reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: None; Publications: 32822602; Phenotypes: Neurodevelopmental disorder with dysmorphic facies, sleep disturbance and brain abnormalities; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.491 KAT5 Sarah Leigh Tag for-review was removed from gene: KAT5.
Early onset or syndromic epilepsy v2.491 KAT5 Sarah Leigh commented on gene: KAT5: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.490 KAT5 Sarah Leigh Source Expert Review Green was added to KAT5.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.170 KAT5 Arina Puzriakova Phenotypes for gene: KAT5 were changed from to 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
Early onset or syndromic epilepsy v2.169 KAT5 Arina Puzriakova Publications for gene: KAT5 were set to
Early onset or syndromic epilepsy v2.168 KAT5 Arina Puzriakova Mode of inheritance for gene: KAT5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Classified gene: KAT5 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Added comment: 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.
Early onset or syndromic epilepsy v2.167 KAT5 Arina Puzriakova Gene: kat5 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.166 KAT5 Arina Puzriakova Tag for-review tag was added to gene: KAT5.
Early onset or syndromic epilepsy v2.143 KAT5 Konstantinos Varvagiannis reviewed gene: KAT5: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 32822602; 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; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.0 KAT8 Konstantinos Varvagiannis gene: KAT8 was added
gene: KAT8 was added to Genetic epilepsy syndromes. 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
Added comment: 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.
Sources: Literature
Early onset or syndromic epilepsy v1.191 KAT5 Rebecca Foulger Source Wessex and West Midlands GLH was added to KAT5.
Early onset or syndromic epilepsy v1.190 KAT5 Rebecca Foulger Source NHS GMS was added to KAT5.
Early onset or syndromic epilepsy v1.189 KAT5 Rebecca Foulger reviewed gene: KAT5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 KAT5 Tracy Lester reviewed gene: KAT5: Rating: RED; Mode of pathogenicity: ; Publications: 28213671, 28195569 ; Phenotypes: Smith-Magenis-like syndrome, schizophrenia; Mode of inheritance: Unknown
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Classified gene: KAT5 as Red List (low evidence)
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Added comment: Comment on list classification: Based on expert reviewers' comments.
Early onset or syndromic epilepsy v0.1469 KAT5 Sarah Leigh Gene: kat5 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy KAT5 Zornitza Stark reviewed gene: KAT5
Early onset or syndromic epilepsy KAT5 Sarah Leigh Added gene to panel