Human Gene Module / Chromosome X / HUWE1

HUWE1HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
14 / 28
Rare Variants / Common Variants
52 / 0
Aliases
HUWE1, RP3-339A18.4,  ARF-BP1,  HECTH9,  HSPC272,  Ib772,  LASU1,  MULE,  URE-B1,  UREB1
Associated Syndromes
Say-Meyer syndrome
Chromosome Band
Xp11.22
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

A de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother (Nava et al., 2012).

Molecular Function

E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins. Regulates neural differentiation and proliferation by catalyzing the polyubiquitination and degradation of MYCN. Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST) [MIM:300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17) [MIM:300705]; also known as mental retardation X-linked type 31 (MRX31).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HUWE1 (28 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation Froyen G , et al. (2008) No -
2 Support Copy-number gains of HUWE1 due to replication- and recombination-based rearrangements Froyen G , et al. (2012) No -
3 Primary Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE Nava C , et al. (2012) Yes ID
4 Recent Recommendation Ubiquitin ligase HUWE1 regulates axon branching through the Wnt/?-catenin pathway in a Drosophila model for intellectual disability Vandewalle J , et al. (2013) No -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
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 High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No Autistic behavior
8 Recent Recommendation The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development Opperman KJ , et al. (2017) No -
9 Recent Recommendation HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients Moortgat S , et al. (2017) No Autistic features, hand stereotypies
10 Support Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome Muthusamy B , et al. (2019) No ASD, ID
11 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
12 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
13 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
14 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
15 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Microcephaly
16 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
17 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes -
18 Support - Alonso-Gonzalez A et al. (2021) Yes -
19 Support - Cerminara M et al. (2021) Yes DD, ID
20 Support - Taşkıran EZ et al. (2021) No Epilepsy/seizures, autistic features
21 Support - Chen S et al. (2021) Yes DD, ID
22 Support - Bruno LP et al. (2021) Yes -
23 Support - Hu C et al. (2022) Yes -
24 Support - Levchenko O et al. (2022) No -
25 Support - Zhou X et al. (2022) Yes -
26 Support - Lucie Sedlackova et al. (2024) Yes -
27 Support - Marketa Wayhelova et al. (2024) No -
28 Support - Axel Schmidt et al. (2024) No DD, cognitive impairment
Rare Variants   (52)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.693+1G>A - splice_site_variant Unknown - - 32477112 Lee J et al. (2020)
c.693+1G>T - splice_site_variant De novo - - 34800434 Chen S et al. (2021)
c.693+1G>T - splice_site_variant De novo - - 31031587 Xiong J , et al. (2019)
c.10580T>C p.Val3527Ala missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.5792A>G p.Lys1931Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Multiplex 22840365 Froyen G , et al. (2012)
c.344C>T p.Ser115Phe missense_variant De novo - - 27620904 Martnez F , et al. (2016)
c.567+1G>C - splice_site_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.6098-20_6109del - splice_site_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.10384A>G p.Ile3462Val missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.3431A>T p.Asp1144Val missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.9208C>T p.Arg3070Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.12344C>T p.Ala4115Val missense_variant De novo - Simplex 31674007 Wu H , et al. (2019)
c.12491_12493del p.Asp4164del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.11911C>T p.Arg3971Trp missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2145C>T p.Pro715%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6659G>T p.Gly2220Val missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2849T>A p.Val950Asp missense_variant De novo - Multiplex 23092983 Nava C , et al. (2012)
c.329G>A p.Arg110Gln missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.344C>T p.Ser115Phe missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.1978G>A p.Gly660Arg missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.2007T>G p.His669Gln missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.1736A>C p.Asn579Thr missense_variant Familial Maternal - 31406558 Munnich A , et al. (2019)
c.3982A>G p.Met1328Val missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.6267T>G p.Ile2089Met missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.9208C>T p.Arg3070Cys missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.9581T>C p.Phe3194Ser missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12205A>T p.Ile4069Phe missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12225C>G p.Asn4075Lys missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12317A>G p.Tyr4106Cys missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12469C>G p.Leu4157Val missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12732G>C p.Glu4244Asp missense_variant De novo - Simplex 29180823 Moortgat S , et al. (2017)
c.12719C>T p.Ser4240Phe missense_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.10485_10487del p.Thr3496del inframe_deletion De novo - Simplex 34948243 Bruno LP et al. (2021)
c.145-2A>G - splice_site_variant Familial Maternal Multiplex 30797980 Muthusamy B , et al. (2019)
c.1708C>T p.Pro570Ser missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.9212G>A p.Arg3071His missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.11832C>G p.Ile3944Met missense_variant De novo - Simplex 38321498 Marketa Wayhelova et al. (2024)
c.12195G>C p.Trp4065Cys missense_variant Familial Maternal - 38008000 Lucie Sedlackova et al. (2024)
c.4095+1G>A - splice_site_variant Familial Maternal Simplex 33739554 Taşkıran EZ et al. (2021)
c.12365G>A p.Arg4122His missense_variant Familial Maternal Simplex 33679889 Cerminara M et al. (2021)
c.12209C>G p.Ser4070Cys missense_variant Familial Maternal Unknown 31906484 Ibarluzea N , et al. (2020)
c.12067C>T p.Arg4023Cys missense_variant Familial Maternal Multiplex 29180823 Moortgat S , et al. (2017)
c.8932del p.Asp2978MetfsTer12 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.8942G>A p.Arg2981His missense_variant Familial Maternal Multi-generational 18252223 Froyen G , et al. (2008)
c.12037C>T p.Arg4013Trp missense_variant Familial Maternal Multi-generational 18252223 Froyen G , et al. (2008)
c.12559C>T p.Arg4187Cys missense_variant Familial Maternal Multi-generational 18252223 Froyen G , et al. (2008)
c.12885G>C p.Lys4295Asn missense_variant Familial Maternal Multi-generational 29180823 Moortgat S , et al. (2017)
c.2007T>G p.His669Gln missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_gain Familial Maternal (3/4), paternal (1/4) 1 simplex, 3 multiplex 22840365 Froyen G , et al. (2012)
c.1125G>T p.Met375Ile missense_variant Familial Maternal Multiplex (monozygotic twins) 31906484 Ibarluzea N , et al. (2020)
c.2429A>C p.Asn810Thr missense_variant Familial Maternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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
S
icon
S

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

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

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Distur2021]
4/1/2020
S
icon
S

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

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

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome.2019] [Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
S
icon
S

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2017
icon
S

Score remained at S

Description

Defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type (MRXST; OMIM 300706], also known as mental retardation and macrocephaly syndrome. MRXST shows clinical variability, and associated phenotypes include macrocephaly and variable contractures. A chromosomal microduplication involving HUWE1 and HSD17B10 is the cause of mental retardation X-linked type 17 (MRX17; OMIM 300705], also known as mental retardation X-linked type 31 (MRX31) (Froyen et al., 2008; Froyen et al., 2012). Clinical assessment of 21 patients with HUWE1 variants in Moortgat et al., 2017 determined that autistic features were reported in seven patients, whereas hand stereotypies were observed in 8 out of 17 patients (47%). A novel, potentially damaging de novo missense variant in HUWE1 was identified in a male ASD proband, but not in the proband's less severely affected brother, in Nava et al., 2012.

Reports Added
[HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.2017]
Krishnan Probability Score

Score 0.491944331016

Ranking 4890/25841 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 19/18225 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 0.95061052794667

Ranking 18560/18665 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
Larsen Cumulative Evidence Score

Score 4

Ranking 310/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.55760656547581

Ranking 217/20870 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
Submit New Gene

Report an Error