Human Gene Module / Chromosome 2 / HECW2

HECW2HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 19
Rare Variants / Common Variants
46 / 0
Aliases
HECW2, NEDL2
Associated Syndromes
-
Chromosome Band
2q32.3
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). Mutations in the HECW2 gene are associated with neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; OMIM 617268) (Halvardson et al., 2016; Berko et al., 2017); some patients with this disorder exhibit behavioral abnormalities including hand-flapping, rocking, self-stimulatory or self-injurious behavior, and autistic features.

Molecular Function

The protein encoded by this gene is a E3 ubiquitin-protein ligase that mediates ubiquitination of TP73. Acts to stabilize TP73 and enhance activation of transcription by TP73.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HECW2 (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Recent Recommendation Mutations in HECW2 are associated with intellectual disability and epilepsy Halvardson J , et al. (2016) No -
4 Recent Recommendation De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia Berko ER , et al. (2016) No Epilepsy/seizures, ASD
5 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
6 Support Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation Nakamura H , et al. (2018) No -
7 Support De Novo HECW2 Mutation Associated With Epilepsy, Developmental Decline, and Intellectual Disability: Case Report and Review of Literature Ullman NL , et al. (2018) No -
8 Support - Brunet T et al. (2021) No -
9 Support - Hiraide T et al. (2021) No -
10 Support - Taşkıran EZ et al. (2021) No ADHD
11 Recent Recommendation - Acharya A et al. (2021) No ASD or autistic features, stereotypy, epilepsy/sei
12 Support - Kritioti E et al. (2021) No Stereotypy
13 Support - Heide EC et al. (2021) No Autistic features, stereotypy
14 Support - Chuan Z et al. (2022) No DD, ID
15 Support - Krgovic D et al. (2022) Yes DD
16 Support - Zhou X et al. (2022) Yes -
17 Support - Sanchis-Juan A et al. (2023) No -
18 Support - et al. () No -
19 Support - et al. () No -
Rare Variants   (46)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4G>A p.Ala2Thr missense_variant Unknown - - 37943464 et al. ()
c.3988C>T p.Arg1330Trp missense_variant Unknown - - 38438125 et al. ()
c.3226-1G>T - splice_site_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.124A>T p.Thr42Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2495C>T p.Thr832Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2591A>C p.Gln864Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1160G>C p.Arg387Thr missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1062C>T p.Asp354%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4128C>T p.Asn1376%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2504G>A p.Arg835Gln missense_variant Unknown - - 34321324 Acharya A et al. (2021)
c.2818G>A p.Ala940Thr missense_variant Unknown - - 34321324 Acharya A et al. (2021)
c.3980T>C p.Phe1327Ser missense_variant Unknown - - 34321324 Acharya A et al. (2021)
c.4436G>A p.Arg1479Gln missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.412A>G p.Ile138Val missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4325A>G p.Asp1442Gly missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3829T>C p.Tyr1277His missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2504G>A p.Arg835Gln missense_variant De novo - Simplex 27389779 Berko ER , et al. (2016)
c.2920C>T p.Arg974Trp missense_variant De novo - Simplex 27389779 Berko ER , et al. (2016)
c.2587T>C p.Tyr863His missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3572G>A p.Arg1191Gln missense_variant De novo - Simplex 27389779 Berko ER , et al. (2016)
c.3988C>T p.Arg1330Trp missense_variant De novo - Simplex 27389779 Berko ER , et al. (2016)
c.4334A>G p.Glu1445Gly missense_variant De novo - Simplex 27389779 Berko ER , et al. (2016)
c.4690G>A p.Glu1564Lys missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.3572G>A p.Arg1191Gln missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3583G>C p.Ala1195Pro missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3597C>A p.Asn1199Lys missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3980T>C p.Phe1327Ser missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3988C>T p.Arg1330Trp missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4323T>G p.Phe1441Leu missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4333G>C p.Glu1445Gln missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4355G>T p.Gly1452Val missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4507A>G p.Thr1503Ala missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4511C>A p.Ser1504Tyr missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.4514G>C p.Ser1505Thr missense_variant De novo - Simplex 34321324 Acharya A et al. (2021)
c.3175C>T p.Pro1059Ser missense_variant Unknown - Unknown 34321324 Acharya A et al. (2021)
c.1105A>G p.Asn369Asp missense_variant De novo - - 33739554 Taşkıran EZ et al. (2021)
c.3571C>T p.Arg1191Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3988C>T p.Arg1330Trp missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.3572G>A p.Arg1191Gln missense_variant De novo - Simplex 29807643 Ullman NL , et al. (2018)
c.3542C>G p.Ala1181Gly missense_variant De novo - Simplex 34324503 Kritioti E et al. (2021)
c.3587A>G p.Lys1196Arg missense_variant De novo - Simplex 34324503 Kritioti E et al. (2021)
c.3988C>T p.Arg1330Trp missense_variant De novo - Simplex 29395664 Nakamura H , et al. (2018)
c.3988C>T p.Arg1330Trp missense_variant De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.4484G>A p.Arg1495Lys missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3571C>T p.Arg1191Trp missense_variant Familial Maternal Multiplex 34327820 Heide EC et al. (2021)
c.3577T>G p.Phe1193Val missense_variant De novo - Multiplex (monozygotic twins) 27389779 Berko ER , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

Score Delta: Score remained at 2

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.

4/1/2021
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021]
1/1/2021
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

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]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
7/1/2016
4
icon
3

Decreased from 4 to 3

Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015). De novo variants in HECW2 have also been identified in patients presenting with epilepsy and intellectual disability (Appenzeller et al., 2014; Wright et al., 2015; Halvardson et al., 2016). Statistical analysis in Halvardson et al., 2016 using a total of 5377 trios yielded an expected number of HECW2 DNMs of 0.7, compared to the observed total of 6 DNMs (p-value of 6.11 x 10-5). Berko et al., 2016 identified six probands with four unique de novo predicted deleterious missense variants in HECW2 from a cohort of 3309 probands with neurodevelopmental disorders (the false discovery rate corrected q-value of the observed six de novo missense variants in this population was calculated to be 6.20E-07 using TADA); all of these probands presented with neurodevelopmental delay and hypotonia, while two of these probands also presented with autism.

Reports Added
[Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia.2016]
1/1/2016
icon
4

Increased from to 4

Description

Two de novo missense variants in the HECW2 gene were identified in simplex ASD probands, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=0.05) (Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.4953444771356

Ranking 3037/25841 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 0.99999585183338

Ranking 386/18225 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 0.90730979531441

Ranking 7185/18665 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 0.57334128450584

Ranking 162/20870 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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