Human Gene Module / Chromosome 2 / DNMT3A

DNMT3ADNA (cytosine-5-)-methyltransferase 3 alpha

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 32
Rare Variants / Common Variants
105 / 1
EAGLE Score
15.9
Strong Learn More
Aliases
DNMT3A, DNMT3A2,  M.HsaIIIA,  TBRS
Associated Syndromes
Tatton-Brown-Rahman syndrome, Heyn-Sproul-Jackson syndrome, DD, Tatton-Brown-Rahman syndrome, DD, Tatton-Brown-Rahman syndrome, ADHD, DD
Chromosome Band
2p23.3
Associated Disorders
SCZ, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Additional de novo protein-truncating variants and missense variants in the DNMT3A gene were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); TADA analysis in both studies identified DNMT3A as a candidate gene with a false discovery rate (FDR) 0.01. 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 Zhou et al., 2022 identified DNMT3A as a gene reaching exome-wide significance (P < 2.5E-06). Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Molecular Function

The protein encoded by this gene is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It plays a role in paternal and maternal imprinting.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DNMT3A (32 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing Jiang YH , et al. (2013) Yes -
2 Support Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability Tatton-Brown K , et al. (2014) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Primary Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
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 Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases Farwell Hagman KD , et al. (2016) No -
8 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
9 Recent Recommendation The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants Tatton-Brown K , et al. (2018) No ASD
10 Support Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions Heyn P , et al. (2018) No Microcephaly, short stature
11 Positive Association Genetic association of DNMT variants can play a critical role in defining the methylation patterns in autism Alex AM , et al. (2019) Yes -
12 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
13 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
14 Support Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients Tenorio J , et al. (2019) No SCZ
15 Support Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes Lane C , et al. (2019) No Autistic traits
16 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
17 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
18 Support Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder Yokoi T et al. (2020) No ASD, ID
19 Support - Smith AM et al. (2021) No ASD, ADHD, OCD, DD, ID
20 Support - Mahjani B et al. (2021) Yes -
21 Support - Bruno LP et al. (2021) No -
22 Support - Leite AJDC et al. (2022) No -
23 Support - Gu T et al. (2022) No -
24 Support - Krgovic D et al. (2022) Yes OCD, DD, ID
25 Support - Levchenko O et al. (2022) No -
26 Support - Zhou X et al. (2022) Yes -
27 Support - Spataro N et al. (2023) No Autistic features
28 Support - Hamagami N et al. (2023) No -
29 Support - Kim GH et al. (2023) No -
30 Support - et al. () No ID, epilepsy/seizures, autistic features
31 Recent Recommendation - et al. () Yes -
32 Support - et al. () No -
Rare Variants   (105)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 34315901 Smith AM et al. (2021)
- - copy_number_loss De novo - - 35390071 Leite AJDC et al. (2022)
- - copy_number_loss De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2141+1G>A - splice_site_variant De novo - Simplex 37795572 et al. ()
- - frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
- p.Arg301Trp missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Arg688His missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Arg736His missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Arg882Cys missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Arg882His missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Cys583Tyr missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Ile310Asn missense_variant Unknown - - 34315901 Smith AM et al. (2021)
- p.Tyr660His missense_variant Unknown - - 34315901 Smith AM et al. (2021)
c.1668-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1015-3C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.2207G>A p.Arg736His missense_variant De novo - Simplex 37795572 et al. ()
c.2036G>A p.Gly679Glu missense_variant De novo - Simplex 38041495 et al. ()
c.1867-284C>A - stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
- p.Phe414fsTer7 frameshift_variant Unknown - - 34315901 Smith AM et al. (2021)
c.1211+2T>G - splice_site_variant De novo - - 31685998 Tenorio J , et al. (2019)
c.1681G>T p.Glu561Ter stop_gained De novo - - 31685998 Tenorio J , et al. (2019)
c.1904G>T p.Arg635Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1919T>C p.Phe640Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2012C>T p.Thr671Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2050G>A p.Val684Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2204A>C p.Tyr735Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2711C>T p.Pro904Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.988T>C p.Trp330Arg missense_variant De novo - - 30478443 Heyn P , et al. (2018)
c.997G>A p.Asp333Asn missense_variant De novo - - 30478443 Heyn P , et al. (2018)
c.1867-254T>C - missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1523T>C p.Leu508Pro missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1034G>T p.Cys345Phe missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.919C>T p.Pro307Ser missense_variant De novo - - 31685998 Tenorio J , et al. (2019)
c.502C>G p.Arg168Gly stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.580G>A p.Asp194Asn stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.941G>A p.Trp314Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1395+3G>C - splice_site_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.556_558+3del - splice_site_variant De novo - Simplex 37303757 Kim GH et al. (2023)
c.745C>T p.Gln249Ter stop_gained De novo - Simplex 32094338 Husson T , et al. (2020)
c.1627G>A p.Gly543Ser missense_variant De novo - - 31685998 Tenorio J , et al. (2019)
c.2207G>A p.Arg736His missense_variant De novo - - 31685998 Tenorio J , et al. (2019)
c.2209C>T p.Leu737Phe missense_variant Unknown - - 31685998 Tenorio J , et al. (2019)
c.1320G>A p.Trp440Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1803G>A p.Trp601Ter stop_gained De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1570C>T p.Arg524Trp missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1660G>A p.Gly554Arg missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.2204A>G p.Tyr735Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2644C>T p.Arg882Cys missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.729T>C p.Thr243= missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2204A>G p.Tyr735Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1443C>A p.Tyr481Ter stop_gained De novo - Simplex 35887114 Levchenko O et al. (2022)
c.1452G>A p.Val484= missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.699dup p.Gly234ArgfsTer19 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1904G>A p.Arg635Gln missense_variant De novo - Simplex 32435502 Yokoi T et al. (2020)
c.541C>T p.Arg181Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.892G>A p.Gly298Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.892G>T p.Gly298Trp missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.901C>T p.Arg301Trp missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.929T>A p.Ile310Asn missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1597G>A p.Gly533Arg missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.1154C>T p.Pro385Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1594G>A p.Gly532Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1643T>A p.Met548Lys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1643T>C p.Met548Thr missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1645T>C p.Cys549Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1684T>C p.Cys562Arg missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1718A>G p.Glu573Gly missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1743G>C p.Trp581Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1748G>A p.Cys583Tyr missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1943T>C p.Leu648Pro missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2094G>C p.Trp698Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2099C>T p.Pro700Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2141C>G p.Ser714Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2188C>T p.Arg730Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2204A>C p.Tyr735Ser missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2207G>A p.Arg736His missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2245C>T p.Arg749Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2309C>T p.Ser770Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2312G>A p.Arg771Gln missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2401A>G p.Met801Val missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2644C>T p.Arg882Cys missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2645G>A p.Arg882His missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2711C>T p.Pro904Leu missense_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1903C>T p.Arg635Trp missense_variant De novo - Simplex 23849776 Jiang YH , et al. (2013)
c.387del p.Glu129AspfsTer35 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.1993G>T p.Val665Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2711C>T p.Pro904Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.892G>T p.Gly298Trp missense_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.1907C>T p.Ala636Val missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.1799_1801del p.Phe600del inframe_deletion De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1969G>A p.Val657Met missense_variant Unknown Not maternal - 35813072 Krgovic D et al. (2022)
c.1067T>C p.Leu356Pro missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1447C>T p.Arg483Trp missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1658T>C p.Ile553Thr missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.221del p.Ala74ValfsTer90 frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2246_2247del p.Arg749ProfsTer7 frameshift_variant De novo - - 31685998 Tenorio J , et al. (2019)
c.421dup p.Glu141GlyfsTer11 frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1262del p.Gln421ArgfsTer78 frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1505dup p.Ile503HisfsTer13 frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.1481G>C p.Cys494Ser missense_variant De novo - Multiplex (monozygotic twins) 37795572 et al. ()
c.402dup p.Gly135TrpfsTer17 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.551_553del p.Pro184_Met185delinsLeu inframe_deletion De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.596_597insGCAA p.Ser199ArgfsTer18 frameshift_variant De novo - - 29900417 Tatton-Brown K , et al. (2018)
c.2296_2297del p.Lys766GlufsTer15 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1127_1128insACGACGACGACGGCTACCAGT p.Tyr376delinsTer inframe_insertion De novo - - 35982159 Zhou X et al. (2022)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1717+26C>T;c.2173+26C>T;c.1606+26C>T - intron_variant - - - 30786140 Alex AM , et al. (2019)
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."

4/1/2020
1
icon
1

Score remained at 1

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder2020]
1/1/2020
1
icon
1

Score remained at 1

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Tatton-Brown-Rahman syndrome: cognitive and behavioural phenotypes.2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients.2019] [New Scoring Scheme]
4/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
1/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Genetic association of DNMT variants can play a critical role in defining the methylation patterns in autism.2019]
10/1/2018
3S
icon
3S

Decreased from 3S to 3S

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Reports Added
[Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions.2018]
7/1/2018
3
icon
3S

Decreased from 3 to 3S

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals.

Reports Added
[Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.2014] [The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.2018]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016]
10/1/2015
icon
3

Increased from to 3

Description

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant.

Krishnan Probability Score

Score 0.48601236988581

Ranking 7261/25841 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 7.7278751608327E-45

Ranking 18212/18225 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
Sanders TADA Score

Score 0.016924415179871

Ranking 32/18665 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 0.51065848971063

Ranking 438/20870 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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