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Intellectual disability - microarray and sequencing v3.43 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; Basilicata-Akhtar syndrome, 301032
Intellectual disability - microarray and sequencing v3.0 MSL3 Louise Daugherty commented on gene: MSL3: As a result of watchlist tag audit the watchlist tag was removed from MSL3- this is now a green gene with sufficient evidence/review
Intellectual disability - microarray and sequencing v3.0 MSL3 Louise Daugherty Tag watchlist was removed from gene: MSL3.
Intellectual disability - microarray and sequencing v3.0 MSL3 Louise Daugherty commented on gene: MSL3: As a result of watchlist tag audit the watchlist tag was removed from MSL3- this is now a green gene with sufficient evidence/review
Intellectual disability - microarray and sequencing v3.0 KAT8 Konstantinos Varvagiannis 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
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].
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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
Intellectual disability - microarray and sequencing v2.744 MSL3 Ivone Leong Classified gene: MSL3 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.744 MSL3 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green based on the new evidence provided by Konstantinos Varvagiannis. MSL3 is not associated with any phenotypes in OMIM; however, it has been confirmed to be associated with a phenotype in Gene2Phenotype with intellectual disability listed as one of the phenotypes.
Intellectual disability - microarray and sequencing v2.744 MSL3 Ivone Leong Gene: msl3 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.684 MSL3 Ivone Leong Phenotypes for gene: MSL3 were changed from to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number
Intellectual disability - microarray and sequencing v2.683 MSL3 Ivone Leong Publications for gene: MSL3 were set to 26350204; 19377476; 28135719; 25529582
Intellectual disability - microarray and sequencing v2.509 MSL3 Konstantinos Varvagiannis reviewed gene: MSL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30224647; Phenotypes: Muscular hypotonia, Feeding difficulties, Neurodevelopmental delay, Intellectual disability; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability - microarray and sequencing v2.468 MSL3 Louise Daugherty Source Victorian Clinical Genetics Services was added to MSL3.
Intellectual disability - microarray and sequencing MSL3 Louise Daugherty classified MSL3 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing MSL3 Louise Daugherty commented on gene: MSL3
Intellectual disability - microarray and sequencing MSL3 Louise Daugherty edited their review of gene: MSL3
Intellectual disability - microarray and sequencing MSL3 Zornitza Stark reviewed gene: MSL3
Intellectual disability - microarray and sequencing MSL3 BRIDGE consortium edited their review of MSL3
Intellectual disability - microarray and sequencing MSL3 BRIDGE consortium reviewed MSL3