Human Gene Module / Chromosome 8 / KAT6A

KAT6AK(lysine) acetyltransferase 6A

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
15 / 32
Rare Variants / Common Variants
146 / 0
Aliases
KAT6A, MOZ,  MRD32,  MYST-3,  MYST3,  RUNXBP2,  ZC2HC6A,  ZNF220
Associated Syndromes
-
Chromosome Band
8p11.21
Associated Disorders
DD/NDD, ID, EP, EPS, 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). 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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases. St. John et al., 2022 described the phenotypic presentation of 49 individuals with pathogenic KAT6A variants and found that developmental delay/intellectual disability (42/45) was the most common phenotype observed in this cohort, along with concerns about vision (37/48), gastrointestinal function (33/48), and sleep (31/48); one-third (10/31) had a diagnosis of autism, and 73% (36/49) were minimally verbal.

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).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KAT6A (32 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
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
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)
9 Recent recommendation KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants Kennedy J , et al. (2018) No ASD or autistic features
10 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
11 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD
12 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No ID
13 Support - Zhou J et al. (2019) Yes -
14 Support Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum Urreizti R , et al. (2020) No Autistic features
15 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes -
16 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
17 Recent Recommendation - Chen X et al. (2021) Yes -
18 Support - Taşkıran EZ et al. (2021) No Epilepsy/seizures, autistic features
19 Support - Zou D et al. (2021) No -
20 Support - Kritioti E et al. (2021) No -
21 Support - Rosenthal SB et al. (2021) Yes -
22 Support - Woodbury-Smith M et al. (2022) Yes -
23 Support - Wang Q et al. (2022) No -
24 Recent Recommendation - St John M et al. (2022) No ASD, ADHD, epilepsy/seizures
25 Support - Zhou X et al. (2022) Yes -
26 Support - Spataro N et al. (2023) No -
27 Support - Costa CIS et al. (2023) Yes -
28 Support - Wang J et al. (2023) Yes -
29 Support - Balasar et al. (2023) No -
30 Support - et al. () Yes -
31 Support - et al. () Yes -
32 Support - et al. () Yes -
Rare Variants   (146)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 35892268 St John M et al. (2022)
- - frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3385C>T p.Arg1129Ter stop_gained De novo - - 38177409 et al. ()
- - splice_site_variant Unknown - - 35892268 St John M et al. (2022)
- - copy_number_loss De novo - Simplex 25728777 Tham E , et al. (2015)
c.1004T>C p.Ile335Thr missense_variant Unknown - - 37943464 et al. ()
- - frameshift_variant Unknown - Simplex 37524782 Balasar et al. (2023)
G>A - intergenic_variant De novo - Simplex 31133750 Zhou J et al. (2019)
- - frameshift_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.751C>T p.Arg251Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.856C>T p.Arg286Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - splice_site_variant De novo - Simplex 34324503 Kritioti E et al. (2021)
c.3456G>A p.Trp1152Ter stop_gained Unknown - - 32477112 Lee J et al. (2020)
- - splice_site_variant De novo - Multiplex 27133397 Millan F , et al. (2016)
c.3385C>T p.Arg1129Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.3385C>T p.Arg1129Ter stop_gained De novo - - 30945278 Jiao Q , et al. (2019)
c.658C>T p.Arg220Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.2437-1G>A - splice_site_variant Unknown - - 35892268 St John M et al. (2022)
c.3353-1G>A - splice_site_variant De novo - - 36980980 Spataro N et al. (2023)
c.907+1del - splice_site_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3661G>A p.Glu1221Lys missense_variant Unknown - Unknown 38287090 et al. ()
c.1136C>G p.Ser379Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.2689G>T p.Glu897Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.805C>T p.Arg269Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.949C>T p.Arg317Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.1364-2A>T - splice_site_variant Unknown - - 30245513 Kennedy J , et al. (2018)
c.1903-1G>A - splice_site_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.443G>A p.Arg148Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.458G>A p.Arg153His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.746C>T p.Thr249Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.815G>A p.Gly272Asp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3040-1_3040del - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.3070C>T p.Arg1024Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3182T>A p.Leu1061Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3338C>G p.Ser1113Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3385C>T p.Arg1129Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3640A>T p.Lys1214Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3661G>T p.Glu1221Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.5617C>T p.Gln1873Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.5639C>A p.Ser1880Ter stop_gained Unknown - - 35892268 St John M et al. (2022)
c.3040-5A>G - splice_region_variant Unknown - - 35892268 St John M et al. (2022)
c.1096C>T p.Arg366Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.2203C>T p.Arg735Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.2492G>C p.Ser831Thr missense_variant De novo - - 33004838 Wang T et al. (2020)
c.3055C>T p.Arg1019Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.3070C>T p.Arg1024Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.3182T>G p.Leu1061Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.3365T>G p.Leu1122Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.3385C>T p.Arg1129Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.3661G>T p.Glu1221Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.4042C>T p.Gln1348Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.4069C>T p.Gln1357Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.4213G>T p.Glu1405Ter stop_gained De novo - - 30245513 Kennedy J , et al. (2018)
c.4381C>T p.Gln1461Ter stop_gained Unknown - - 30245513 Kennedy J , et al. (2018)
c.3076C>T p.Arg1026Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3202G>T p.Asp1068Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3203A>G p.Asp1068Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1748G>A p.Gly583Glu missense_variant Unknown - - 35892268 St John M et al. (2022)
c.4108G>T p.Glu1370Ter stop_gained De novo - Simplex 25728777 Tham E , et al. (2015)
c.4653T>G p.Ser1551Arg missense_variant Unknown - - 35892268 St John M et al. (2022)
c.4664G>A p.Ser1555Asn missense_variant Unknown - - 35892268 St John M et al. (2022)
c.5212G>A p.Asp1738Asn missense_variant Unknown - - 35892268 St John M et al. (2022)
c.1903-5_1903-2del - splice_site_variant Unknown - - 35892268 St John M et al. (2022)
c.2683C>T p.Pro895Ser missense_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.20del p.Pro7ArgfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4645G>A p.Gly1549Ser missense_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.4653T>G p.Ser1551Arg missense_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.4672A>C p.Ser1558Arg missense_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3070C>T p.Arg1024Ter stop_gained De novo - Simplex 27133397 Millan F , et al. (2016)
c.1312C>T p.Arg438Ter stop_gained De novo - - 33739554 Taşkıran EZ et al. (2021)
c.1582C>T p.Pro528Ser missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.4665C>G p.Ser1555Arg missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.458G>T p.Arg153Leu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.2558dup p.His853GlnfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.553C>T p.Leu185Phe missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.3385C>T p.Arg1129Ter stop_gained De novo - Simplex 32041641 Urreizti R , et al. (2020)
c.3640A>T p.Lys1214Ter stop_gained De novo - Simplex 32041641 Urreizti R , et al. (2020)
c.1506del p.Asp503IlefsTer42 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.46del p.Ala16ProfsTer5 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
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.1928A>G p.Asn643Ser missense_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.195_198del p.Asn65LysfsTer15 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.4025dup p.Glu1343GlyfsTer13 frameshift_variant De novo - - 28991257 Jin SC , et al. (2017)
c.1285dup p.Glu429GlyfsTer7 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3631_3632del p.Val1211Ter frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.5248_5257del p.Thr1750Ter frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3038A>G p.Lys1013Arg missense_variant De novo - Simplex 37280359 Costa CIS et al. (2023)
c.1136C>A p.Ser379Ter stop_gained Unknown Not maternal - 30245513 Kennedy J , et al. (2018)
c.3434del p.Pro1145LeufsTer2 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4219del p.Ile1407SerfsTer3 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4361dup p.Thr1455AspfsTer9 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.2911dup p.Arg971ProfsTer5 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.1075G>A p.Gly359Ser missense_variant De novo - Simplex 32041641 Urreizti R , et al. (2020)
c.2397C>T p.Asn799%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3596del p.Gly1199AspfsTer95 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4025del p.Lys1342ArgfsTer11 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4144dup p.Thr1382AsnfsTer12 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4224dup p.Leu1409IlefsTer10 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.1112C>A p.Ser371Tyr missense_variant Familial Maternal - 30245513 Kennedy J , et al. (2018)
c.1507del p.Asp503IlefsTer42 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.1819dup p.Tyr607LeufsTer16 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3286dup p.Cys1096LeufsTer6 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3434del p.Pro1145LeufsTer2 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3515del p.Gly1172AspfsTer4 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.4362dup p.Thr1455AspfsTer9 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.1A>G p.Met1? initiator_codon_variant Familial Paternal - 30245513 Kennedy J , et al. (2018)
c.3989_3990del p.Lys1330ArgfsTer25 frameshift_variant Unknown - - 34145886 Zou D et al. (2021)
c.4025del p.Lys1342ArgfsTer11 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3385C>T p.Arg1129Ter stop_gained De novo - Simplex 33739554 Taşkıran EZ et al. (2021)
c.195_198del p.Asn65LysfsTer15 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.1639_1640del p.Met547GlufsTer3 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4292dup p.Leu1431PhefsTer8 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
c.1951_1954del p.Pro651AsnfsTer47 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4228_4232del p.Lys1410GlyfsTer7 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.1639_1640del p.Met547GlufsTer3 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.287del p.Asn96MetfsTer7 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3879dup p.Glu1294ArgfsTer19 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
c.4031_4032del p.Glu1344AlafsTer11 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4254_4257del p.Glu1419TrpfsTer12 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.5505_5508del p.Asn1836LeufsTer15 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3286_3287insC p.Cys1096SerfsTer6 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4228_4232del p.Lys1410GlyfsTer7 frameshift_variant Unknown - - 30245513 Kennedy J , et al. (2018)
c.1283_1284insT p.Glu429GlyfsTer7 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3349_3350insCA p.Asp1117AlafsTer7 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4254_4257del p.Glu1419TrpfsTer12 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.4273_4274del p.Val1425ThrfsTer13 frameshift_variant Unknown - - 30245513 Kennedy J , et al. (2018)
c.5505_5508del p.Asn1836LeufsTer15 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3286_3287insC p.Cys1096SerfsTer6 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3399_3400insGA p.Lys1134GlufsTer14 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3462del p.Gly1155AlafsTer21 frameshift_variant De novo - Simplex 27133397 Millan F , et al. (2016)
c.3921_3922del p.Glu1307AspfsTer5 frameshift_variant De novo - Simplex 35266334 Wang Q et al. (2022)
c.4091_4092insAGAA p.Asp1365LysfsTer3 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4311_4314del p.Glu1438MetfsTer94 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1308_1309insCGCAA p.Tyr437ArgfsTer43 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.3555dup p.Ala1186SerfsTer5 frameshift_variant De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.4256_4257insAGCTG p.Leu1420AlafsTer14 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.1308_1309insCGCAA p.Tyr437ArgfsTer43 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3655del p.Leu1219TyrfsTer75 frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.3830_3831insTT p.Arg1278SerfsTer17 frameshift_variant De novo - Simplex 25728777 Tham E , et al. (2015)
c.5645_5646delTTins10 p.Glu1419TrpfsTer12 frameshift_variant Unknown - - 35892268 St John M et al. (2022)
c.4043_4044del p.Gln1348ArgfsTer7 frameshift_variant Familial Maternal - 30245513 Kennedy J , et al. (2018)
c.4254_4257del p.Glu1419TrpfsTer12 frameshift_variant De novo - Simplex 32041641 Urreizti R , et al. (2020)
c.3345_3346insAGTCAGATGA p.Ala1116SerfsTer5 frameshift_variant De novo - - 30245513 Kennedy J , et al. (2018)
c.3427_3428insTA p.Ser1143LeufsTer5 frameshift_variant De novo - Simplex 32041641 Urreizti R , et al. (2020)
c.3116_3117del p.Ser1039Ter frameshift_variant De novo - Multiplex (monozygotic twins) 25728777 Tham E , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, 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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

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."

4/1/2021
2S
icon
2S

Score remained at 2S

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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021]
10/1/2020
2S
icon
2S

Score remained at 2S

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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
2S
icon
2S

Score remained at 2S

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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy2020]
1/1/2020
2S
icon
2S

Score remained at 2S

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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum.2020]
10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[New Scoring Scheme]
4/1/2019
3S
icon
3S

Decreased from 3S 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. 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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019] [The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
10/1/2018
3S
icon
3S

Decreased from 3S 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. 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. A review of the clinical phenotypes of 52 previously unreported individuals with pathogenic KAT6A variants in Kennedy et al., 2018 found that autism and autistic features were reported in approximately 25% of cases.

Reports Added
[KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
3S
icon
3S

Decreased from 3S 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. 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.

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
10/1/2016
3S
icon
3S

Decreased from 3S 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. 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.

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
3S
icon
3S

Decreased from 3S 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. 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.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
3S
icon
3S

Decreased from 3S 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. 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.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.2015] [Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder.2016]
1/1/2016
3S
icon
3S

Decreased from 3S 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.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.2015] [Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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