HECW2HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2
Autism Reports / Total Reports
5 / 20Rare Variants / Common Variants
47 / 0Aliases
HECW2, NEDL2Associated Syndromes
-Chromosome Band
2q32.3Associated Disorders
DD/NDD, ADHD, ID, EPS, ASDRelevance 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
SFARI Genomic Platforms
Reports related to HECW2 (20 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 | - | Taà Ÿkñran 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 | - | Karthika Ajit Valaparambil et al. () | No | - |
19 | Support | - | Tamam Khalaf et al. (2024) | No | - |
20 | Support | - | Marta Viggiano et al. (2024) | Yes | ID |
Rare Variants (47)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
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.3988C>T | p.Arg1330Trp | missense_variant | Unknown | - | - | 38438125 | Tamam Khalaf et al. (2024) | |
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 | Taà Ÿkñran EZ et al. (2021) | |
c.4G>A | p.Ala2Thr | missense_variant | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
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.2426T>C | p.Leu809Pro | missense_variant | De novo | - | Simplex | 38519481 | Marta Viggiano et al. (2024) | |
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
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 criteriaWe 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
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.
1/1/2021
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.
10/1/2019
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
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.
7/1/2016
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.
1/1/2016
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]
ExAC Score
Score 0.99999585183338
Ranking 386/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.90730979531441
Ranking 7185/18665 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.57334128450584
Ranking 162/20870 scored genes
[Show Scoring Methodology]