Human Gene Module / Chromosome 11 / KMT2A

KMT2ALysine (K)-specific methyltransferase 2A

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
17 / 53
Rare Variants / Common Variants
198 / 0
Aliases
KMT2A, hCG_1732268,  ALL-1,  CXXC7,  HRX,  HTRX1,  MLL,  MLL/GAS7,  MLL1,  MLL1A,  TET1-MLL,  TRX1,  WDSTS
Associated Syndromes
Wiedemann-Steiner syndrome, Rubinstein-Taybisyndrome, Wiedemann-Steiner syndrome, DD, ID
Chromosome Band
11q23.3
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Relevance to Autism

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2). A retrospective, multicenter, observational study of 104 individuals with Wiedemann-Steiner syndrome from five continents in Sheppard et al., 2021 found that 21.3% of individuals in this cohort presented with autism spectrum disorder. Additional de novo loss-of-function variants in the KMT2A gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KMT2A as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis via its histone H3 lysine 4 (H3K4) methyltransferase activity, which mediates chromatin modifications associated with epigenetic transcriptional activation. Mutations in this gene are associated with Wiedemann-Steiner syndrome (OMIM:605130), a syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KMT2A (53 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations in MLL cause Wiedemann-Steiner syndrome Jones WD , et al. (2012) No DD, ID, ASD
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Recent Recommendation Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) Yes -
5 Support Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations Miyake N , et al. (2015) No DD, ID
6 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
7 Support Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype of Wiedemann-Steiner syndrome Steel D , et al. (2015) No DD
8 Support Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A Stellacci E , et al. (2016) No Epilepsy/seizures, microcephaly, DD, ID
9 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
10 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
11 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, ID
12 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
13 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)
14 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No -
15 Support Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome Lebrun N , et al. (2017) No ID, hypotonia, stereotypies
16 Recent Recommendation Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases Baer S , et al. (2018) No ASD
17 Support Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients Li N , et al. (2018) No -
18 Support A novel deletion mutation in KMT2A identified in a child with ID/DD and blood eosinophilia Zhang H , et al. (2019) No Stereotypies
19 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD
20 Recent Recommendation Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants Chan AJS , et al. (2019) No ASD, ID, ADHD
21 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
22 Support Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes Di Fede E et al. (2020) No ASD, DD, ID
23 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
24 Support - Brunet T et al. (2021) No -
25 Support - Hiraide T et al. (2021) No ASD, epilepsy/seizures
26 Support - Chen JS et al. (2021) Yes -
27 Recent Recommendation - Sheppard SE et al. (2021) No ASD
28 Support - Valentino F et al. (2021) No -
29 Support - Rosenthal SB et al. (2021) Yes -
30 Support - Luo S et al. (2021) No -
31 Support - Pode-Shakked B et al. (2021) Yes -
32 Support - Mahjani B et al. (2021) Yes -
33 Support - Bruno LP et al. (2021) No -
34 Support - Li D et al. (2022) Yes -
35 Support - Foroutan A et al. (2022) No -
36 Support - Woodbury-Smith M et al. (2022) Yes -
37 Support - Verberne EA et al. (2022) No -
38 Support - Chuan Z et al. (2022) No DD, ID
39 Support - Durand B et al. (2022) No ASD
40 Support - Zhou X et al. (2022) Yes -
41 Support - Li S et al. (2023) No Stereotypy
42 Support - Spataro N et al. (2023) No Epilepsy/seizures
43 Support - Hu C et al. (2023) Yes -
44 Support - Lin Y et al. (2023) No ASD, epilepsy/seizures
45 Support - Ng R et al. (2023) No -
46 Support - Cirnigliaro M et al. (2023) Yes -
47 Support - Amerh S Alqahtani et al. (2023) No -
48 Support - Lucie Sedlackova et al. (2024) No -
49 Support - M Cecilia Poli et al. () No -
50 Support - Tamam Khalaf et al. (2024) No -
51 Support - Ruohao Wu et al. (2024) Yes -
52 Support - Alistair T Pagnamenta et al. (2024) No Autistic features
53 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (198)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 37025457 Lin Y et al. (2023)
c.901C>T p.Arg301Ter stop_gained De novo - - 30305169 Li N , et al. (2018)
c.883A>T p.Lys295Ter stop_gained De novo - - 34469078 Luo S et al. (2021)
c.10900+2T>C - splice_site_variant De novo - - 30305169 Li N , et al. (2018)
c.3335-1G>C - splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.4576-1G>C - splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.5363+1del - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.269C>A p.Ser90Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.4012+1del - frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.3241C>T p.Arg1081Ter stop_gained De novo - - 30305169 Li N , et al. (2018)
c.5871T>A p.Tyr1957Ter stop_gained De novo - - 30305169 Li N , et al. (2018)
c.4171C>T p.Gln1391Ter stop_gained De novo - - 34469078 Luo S et al. (2021)
c.478C>T p.Arg160Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.3334+1G>A - splice_site_variant De novo - - 29158550 Popp B , et al. (2017)
c.4696+1G>A - splice_site_variant De novo - - 29574747 Baer S , et al. (2018)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
c.10837C>T p.Gln3613Ter stop_gained Unknown - - 30305169 Li N , et al. (2018)
c.4906C>T p.Arg1636Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.5251A>T p.Lys1751Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.7438C>T p.Arg2480Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.368G>A p.Gly123Asp missense_variant Unknown - - 34968013 Li D et al. (2022)
c.3301C>T p.Arg1101Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.4897C>T p.Arg1633Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.6487C>T p.Arg2163Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.7438C>T p.Arg2480Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.7630G>T p.Glu2544Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.7975C>T p.Arg2659Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.4906C>T p.Arg1636Ter stop_gained De novo - - 35571021 Chuan Z et al. (2022)
c.553C>T p.Arg185Ter stop_gained De novo - - 32641752 Di Fede E et al. (2020)
c.4897C>T p.Arg1633Ter stop_gained De novo - - 26690532 Steel D , et al. (2015)
c.2452A>T p.Lys818Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.11322-1G>A - splice_site_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.488C>A p.Thr163Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.991C>T p.Arg331Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6781C>T p.Gln2261Ter stop_gained De novo - - 25810209 Miyake N , et al. (2015)
c.7438C>T p.Arg2480Ter stop_gained De novo - - 25810209 Miyake N , et al. (2015)
c.8095C>T p.Arg2699Ter stop_gained De novo - - 31044088 Chan AJS , et al. (2019)
c.3596G>A p.Trp1199Ter stop_gained De novo - - 32641752 Di Fede E et al. (2020)
c.11702A>C p.His3901Pro missense_variant De novo - - 37007974 Hu C et al. (2023)
c.3503G>A p.Gly1168Asp missense_variant De novo - - 30305169 Li N , et al. (2018)
c.3499T>C p.Cys1167Arg missense_variant De novo - - 34469078 Luo S et al. (2021)
c.3570-1G>C - splice_site_variant De novo - Simplex 37025457 Lin Y et al. (2023)
c.2944T>A p.Ser982Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11716C>T p.Arg3906Cys missense_variant De novo - - 30305169 Li N , et al. (2018)
c.2641G>T p.Glu881Ter stop_gained De novo - Simplex 37025457 Lin Y et al. (2023)
c.3191G>C p.Arg1064Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3191G>T p.Arg1064Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3199C>T p.Arg1067Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3545G>A p.Arg1182His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4048C>T p.Arg1350Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4334T>C p.Phe1445Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4594C>T p.Arg1532Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.4777C>T p.Arg1593Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4862C>A p.Ala1621Asp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4888C>T p.Arg1630Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4907G>A p.Arg1636Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4972C>T p.Arg1658Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5057G>A p.Arg1686His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6067C>T p.His2023Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6200G>A p.Arg2067His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6446G>A p.Arg2149Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6590G>A p.Arg2197His missense_variant De novo - - 33004838 Wang T et al. (2020)
c.6590G>C p.Arg2197Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6619C>T p.Arg2207Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6632G>A p.Arg2211Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7873C>T p.Arg2625Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8818C>T p.Arg2940Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.9334A>G p.Ser3112Gly missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2618G>T p.Ser873Ile missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3409A>T p.Arg1137Ter stop_gained De novo - Simplex 37025457 Lin Y et al. (2023)
c.4504C>T p.Arg1502Ter stop_gained De novo - Simplex 37025457 Lin Y et al. (2023)
c.5431C>T p.Arg1811Ter stop_gained De novo - Simplex 37025457 Lin Y et al. (2023)
c.10208C>T p.Pro3403Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.10634G>A p.Arg3545Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11246G>A p.Arg3749His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11293G>A p.Gly3765Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11530C>T p.Arg3844Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11531G>A p.Arg3844Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11804G>A p.Arg3935His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2115dup p.Glu706Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3460C>T p.Arg1154Trp missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3464G>A p.Cys1155Tyr missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3542G>A p.Gly1181Asp missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.5873A>G p.His1958Arg missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.6080G>A p.Gly2027Glu missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.838C>A p.Pro280Thr missense_variant Unknown - - 25810209 Miyake N , et al. (2015)
c.4207_4218+22dup - frameshift_variant Unknown - - 28263302 C Yuen RK et al. (2017)
c.3633_3634+3del - splice_site_variant De novo - - 32641752 Di Fede E et al. (2020)
c.3301C>T p.Arg1101Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.11206C>T p.Gln3736Ter stop_gained De novo - Simplex 37025457 Lin Y et al. (2023)
c.3801C>T p.Val1267%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.478C>T p.Arg160Ter stop_gained De novo - Simplex 34948243 Bruno LP et al. (2021)
c.3566G>A p.Cys1189Tyr missense_variant De novo - - 25810209 Miyake N , et al. (2015)
c.3460C>T p.Arg1154Trp missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.3581G>A p.Cys1194Tyr missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.8558T>G p.Met2853Arg missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.8543T>C p.Leu2848Pro missense_variant De novo - - 31044088 Chan AJS , et al. (2019)
c.3472T>C p.Cys1158Arg missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.10780C>T p.Gln3594Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.11555T>C p.Ile3852Thr missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.8561A>G p.Asp2854Gly missense_variant De novo - Simplex 36625521 Li S et al. (2023)
c.4819+2_4819+3delinsGG - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.7144C>T p.Arg2382Ter stop_gained De novo - Simplex 22795537 Jones WD , et al. (2012)
c.2944T>A p.Ser982Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2510dup p.Trp838LeufsTer9 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.3463T>A p.Cys1155Ser missense_variant De novo - Simplex 37025457 Lin Y et al. (2023)
c.3503G>T p.Gly1168Val missense_variant De novo - Simplex 37025457 Lin Y et al. (2023)
c.3509G>T p.Cys1170Phe missense_variant De novo - Simplex 37025457 Lin Y et al. (2023)
c.69dup p.Arg24AlafsTer123 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3481T>G p.Cys1161Gly missense_variant De novo - - 27320412 Stellacci E , et al. (2016)
c.8531G>T p.Cys2844Phe missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3478G>A p.Gly1160Ser missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.2318dup p.Ser774ValfsTer12 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.4061del p.Pro1354LeufsTer2 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.6052del p.Glu2018AsnfsTer7 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.6476C>A p.Ser2159Tyr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6665dup p.Tyr2222Ter frameshift_variant De novo - - 35253369 Verberne EA et al. (2022)
c.3837del p.Pro1281LeufsTer75 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.10752dup p.Gly3585ArgfsTer8 frameshift_variant De novo - - 30305169 Li N , et al. (2018)
c.2318dup p.Ser774ValfsTer12 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.7007dup p.Gln2337ThrfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2318dup p.Ser774ValfsTer12 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.10319T>C p.Ile3440Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1142dup p.Ala383GlyfsTer6 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.4907G>A p.Arg1636Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.9661del p.Leu3221SerfsTer35 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.9274dup p.Tyr3092LeufsTer21 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.10064dup p.Thr3356TyrfsTer3 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.5787del p.Arg1930GlyfsTer5 frameshift_variant De novo - - 28991257 Jin SC , et al. (2017)
c.2318dup p.Ser774ValfsTer12 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.4032del p.Val1347TrpfsTer9 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.5603del p.Pro1868GlnfsTer3 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.8270dup p.Ile2758AspfsTer2 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.6463C>G p.Pro2155Ala missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.5251A>T p.Lys1751Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.2483C>G p.Ser828Ter stop_gained De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.2162G>A p.Arg721Gln missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.585_586del p.Ser197ProfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.9575A>C p.Gln3192Pro missense_variant De novo - Simplex 32094338 Husson T , et al. (2020)
c.3448C>T p.Arg1150Cys missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1038del p.Val347LeufsTer53 frameshift_variant De novo - - 25810209 Miyake N , et al. (2015)
c.2148del p.Leu717CysfsTer39 frameshift_variant De novo - - 25810209 Miyake N , et al. (2015)
c.6169del p.Val2057TyrfsTer18 frameshift_variant De novo - - 28263302 C Yuen RK et al. (2017)
c.6169del p.Val2057TyrfsTer18 frameshift_variant De novo - - 31044088 Chan AJS , et al. (2019)
c.3604del p.Ser1202ProfsTer12 frameshift_variant De novo - - 32641752 Di Fede E et al. (2020)
c.9274dup p.Tyr3092LeufsTer21 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.4599dup p.Lys1534Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.8267del p.Leu2756Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.6534dup p.Val2179SerfsTer5 frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.6261C>T p.Asn2087%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1701_1702del p.Pro568ThrfsTer12 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.77del p.Gly26AlafsTer2 frameshift_variant De novo - Simplex 30841869 Zhang H , et al. (2019)
c.10324del p.Ala3442ProfsTer17 frameshift_variant De novo - - 31044088 Chan AJS , et al. (2019)
c.10835+1G>A - splice_site_variant Familial Paternal Simplex 32094338 Husson T , et al. (2020)
c.9682del p.Arg3228ValfsTer28 frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.1844del p.Pro615ArgfsTer8 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
- - copy_number_loss De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5896_5897dup p.Asn1966LysfsTer19 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4667_4668del p.Cys1556SerfsTer2 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.6002_6005del p.Phe2001TrpfsTer8 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.5256del p.Ala1753ProfsTer70 frameshift_variant De novo - - 34356170 Valentino F et al. (2021)
c.2461dup p.Ser821LysfsTer11 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3473G>A p.Cys1158Tyr missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.4038dup p.Val1347SerfsTer24 frameshift_variant De novo - Simplex 37025457 Lin Y et al. (2023)
c.3895_3896del p.Ser1299ProfsTer26 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.8174_8177del p.Asp2725GlyfsTer31 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.9714_9735del p.Pro3239LeufsTer10 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.654_679delinsT p.Glu219ProfsTer5 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.1697_1717dup p.Leu566_Leu572dup inframe_insertion Unknown - - 32641752 Di Fede E et al. (2020)
c.4048del p.Arg1350AlafsTer6 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.2958_2974delinsA p.Lys987ProfsTer15 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.10324del p.Ala3442ProfsTer17 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.9440C>T p.Ser3147Phe missense_variant Familial Maternal Simplex 29574747 Baer S , et al. (2018)
c.5256dup p.Ala1753SerfsTer32 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.7686_7687del p.Glu2563LysfsTer14 frameshift_variant De novo - - 28263302 C Yuen RK et al. (2017)
c.7087_7090del p.Ser2363LeufsTer12 frameshift_variant De novo - - 31044088 Chan AJS , et al. (2019)
c.7695_7696del p.Glu2566LysfsTer14 frameshift_variant De novo - - 31044088 Chan AJS , et al. (2019)
c.3902_3905dup p.Leu1303SerfsTer24 frameshift_variant Unknown - - 32641752 Di Fede E et al. (2020)
c.8806_8809del p.Val2936Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.10298C>G p.Pro3433Arg missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.10850T>C p.Leu3617Pro missense_variant Familial Maternal Simplex 29574747 Baer S , et al. (2018)
c.6913del p.Ser2305LeufsTer2 frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.2565dup p.Glu856ArgfsTer10 frameshift_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.5874_5878del p.Phe1959ValfsTer12 frameshift_variant De novo - - 38177409 M Cecilia Poli et al. ()
c.5364-2A>G - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3460C>T p.Arg1154Trp missense_variant Familial Paternal Multiplex 29574747 Baer S , et al. (2018)
c.2530del p.Gln844ArgfsTer105 frameshift_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.10487dup p.Met3496IlefsTer43 frameshift_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.2514del p.Trp838CysfsTer111 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.8864_8868del p.Ile2955ArgfsTer18 frameshift_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.4551del p.Lys1517AsnfsTer69 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.8724del p.Glu2908AspfsTer21 frameshift_variant De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.173dup p.Ala59GlyfsTer88 frameshift_variant Familial - Unknown 37799141 Amerh S Alqahtani et al. (2023)
c.2758G>T p.Asp920Tyr stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.6571C>T p.Arg2191Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2126_2127del p.Ser709Ter frameshift_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.2627_2630del p.Arg876ThrfsTer72 frameshift_variant De novo - Multiplex (monozygotic twins) 36625521 Li S et al. (2023)
c.10234dup p.Leu3412ProfsTer17 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
1
icon
1

Score remained at 1

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

Reports Added
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021] [Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome2021]
1/1/2021
1
icon
1

Score remained at 1

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

Reports Added
[Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes2020]
1/1/2020
1
icon
1

Score remained at 1

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

Reports Added
[Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2).

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

Score remained at 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944)

Reports Added
[A novel deletion mutation in KMT2A identified in a child with ID/DD and blood eosinophilia.2019] [Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019] [Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.2019]
10/1/2018
1S
icon
1S

Score remained at 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944)

Reports Added
[Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients.2018]
10/1/2017
1S
icon
1S

Score remained at 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944)

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]
4/1/2017
2S
icon
1S

Decreased from 2S to 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537. Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo mutations in MLL cause Wiedemann-Steiner syndrome.2012] [Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype ...2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A.2016] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
10/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A.2016]
1/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo mutations in MLL cause Wiedemann-Steiner syndrome.2012] [Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype ...2015]
1/1/2015
icon
2S

Increased from to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

Krishnan Probability Score

Score 0.61112172006711

Ranking 205/25841 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 1

Ranking 9/18225 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 0.999

Ranking 4/239 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 0.18886989801149

Ranking 105/18665 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
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