Human Gene Module / Chromosome 8 / KAT6A

KAT6AK(lysine) acetyltransferase 6A

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 8
Rare Variants / Common Variants
20 / 0
Aliases
KAT6A, MOZ,  MRD32,  MYST-3,  MYST3,  RUNXBP2,  ZC2HC6A,  ZNF220
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
8p11.21
Associated Disorders
DD/NDD, ASD
Relevance to Autism

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Furthermore, one of the four patients with a de novo KAT6A nonsense variant identified in Arboleda et al., 2015 was diagnosed with ASD.

Molecular Function

This gene encodes a member of the MOZ, YBFR2, SAS2, TIP60 family of histone acetyltransferases and is part of a complex that acetylates lysine-9 residues in histone 3. In addition, it acts as a co-activator for several transcription factors. Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268).

Reports related to KAT6A (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
2 Support De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. Arboleda VA , et al. (2015) No ASD (1 case)
3 Support Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Tham E , et al. (2015) No Microcephaly, craniosynostosis, hypotonia, feeding
4 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
5 Support Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder. Millan F , et al. (2016) No ASD (1 case)
6 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
7 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No Delayed speech and language development, motor del
8 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
del(4) - frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3385C>T p.Arg1129Ter stop_gained De novo - Simplex 25728775 Arboleda VA , et al. (2015)
c.3385C>T p.Arg1129Ter stop_gained De novo - Simplex 25728775 Arboleda VA , et al. (2015)
c.3070C>T p.Arg1024Ter stop_gained De novo - Simplex 25728775 Arboleda VA , et al. (2015)
c.3385C>T p.Arg1129Ter stop_gained De novo - Simplex 25728775 Arboleda VA , et al. (2015)
c.3879dupA p.Glu1294ArgfsTer19 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
c.3116_3117delCT p.Ser1039Ter frameshift_variant De novo - Multiplex (monozygotic twins) 25728777 Tham E , et al. (2015)
c.4292dupT p.Leu1431PhefsTer8 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
c.4108G>T p.Glu1370Ter stop_gained De novo - Simplex 25728777 Tham E , et al. (2015)
c.3830_3831insTT p.Arg1278SerfsTer17 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
- - copy_number_loss De novo - Simplex 25728777 Tham E , et al. (2015)
c.3462delA p.Gly1155AlafsTer21 frameshift_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.3287delG p.Cys1096PhefsTer27 frameshift_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.3230delA p.Asn1077MetfsTer46 frameshift_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.3070C>T p.Arg1024Ter stop_gained De novo - Simplex 27133397 Millan F , et al. (2016)
c.1928A>G p.Asn643Ser missense_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.3040-1_3040delGA - splice_site_variant De novo - Multiplex 27133397 Millan F , et al. (2016)
c.4665C>G p.Ser1555Arg missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.3655del p.Leu1219TyrfsTer75 frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
insT p.Lys1342fs frameshift_variant De novo - - 28991257 Jin SC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD. An additional patient with ASD, intellectual disability, and epilepsy was found to have a de novo splice-site variant in KAT6A in Millan et al., 2016; however, this patient also had a sister with ID and autism, and the presence of the KAT6A variant in her was not reported.

Score Delta: Score remained at 3S

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017
3S
icon
3S

Score remained at 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD. An additional patient with ASD, intellectual disability, and epilepsy was found to have a de novo splice-site variant in KAT6A in Millan et al., 2016; however, this patient also had a sister with ID and autism, and the presence of the KAT6A variant in her was not reported.

10/1/2016
3S
icon
3S

Score remained at 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD. An additional patient with ASD, intellectual disability, and epilepsy was found to have a de novo splice-site variant in KAT6A in Millan et al., 2016; however, this patient also had a sister with ID and autism, and the presence of the KAT6A variant in her was not reported.

7/1/2016
3S
icon
3S

Score remained at 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD. An additional patient with ASD, intellectual disability, and epilepsy was found to have a de novo splice-site variant in KAT6A in Millan et al., 2016; however, this patient also had a sister with ID and autism, and the presence of the KAT6A variant in her was not reported.

4/1/2016
3S
icon
3S

Score remained at 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD. An additional patient with ASD, intellectual disability, and epilepsy was found to have a de novo splice-site variant in KAT6A in Millan et al., 2016; however, this patient also had a sister with ID and autism, and the presence of the KAT6A variant in her was not reported.

1/1/2016
3S
icon
3S

Score remained at 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD.

7/1/2015
icon
3S

Increased from to 3S

Description

A de novo frameshift variant in the KAT6A gene has been identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). Variants in this gene are associated with autosomal dominant mental retardation-32 (MRD32; OMIM 616268). One of the four patients with a de novo KAT6A nonsense variant and intellectual disability that was identified in Arboleda et al., 2015 was also diagnosed with ASD.

Krishnan Probability Score

Score 0.61090113094443

Ranking 214/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999998463162

Ranking 146/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.991

Ranking 25/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.67769008339942

Ranking 1028/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.41023951066219

Ranking 1343/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with KAT6A(1 CNVs)
8p11.21 9 Deletion 18  /  26
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