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Intellectual disability syndromic and non-syndromic

Gene: HECW2

Green List (high evidence)

HECW2 (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2)
EnsemblGeneIds (GRCh38): ENSG00000138411
EnsemblGeneIds (GRCh37): ENSG00000138411
OMIM: 617245, Gene2Phenotype
HECW2 is in 6 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Two probands reported with biallelic variants and putative loss of function mechanism of disease (compared to the established gain of function monoallelic disease)
PMID: 35753050 - Caucasian girl who presented a severe neurodevelopmental disorder with drug-resistant epilepsy, hypotonia, severe gastro-esophageal reflux and brain magnetic resonance imaging anomalies with a homozygous splice variant that causes in-frame elimination of exon 22 (c.3917+2_3917+12delinsG r.3766_3917+1del p.Leu1256_Trp1306del). Protein expression level was reduced by 60%, suggesting a partial loss-of-function mechanism of disease.
PMID: 35487419 - homozygous nonsense variant (c.736C>T; p.Arg246*) identified in a proband from a Moroccan consanguineous family, with developmental delay, intellectual disability, hypotonia, generalized tonico-clonic seizures and a persistent tilted head.

Association with bi-allelic variants is AMBER.
Created: 10 Oct 2022, 9:15 a.m. | Last Modified: 10 Oct 2022, 9:16 a.m.
Panel Version: 0.4987
Typically denovo missense variants in the HECT domain.
PMID: 29807643 - R1191Q single case with severe D/ID, EE and regression
PMID: 29395664 - single case with regression, loss of swallowing, increased abnormal movements/hand stereotypies, Rett like, cortical visual impairment and EE
PMID: 27334371 - propose GOF or dominant negative; 1 case plus references 5 previous cases
PMID: 27389779 - four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. p. Arg1330Trp, p.Glu1445Gly reported >1 case.
Regression reported in the context of refractory EE
Created: 19 Oct 2020, 4:12 a.m. | Last Modified: 19 Oct 2020, 4:12 a.m.
Panel Version: 0.3081

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with hypotonia, seizures, and absent language, MIM# 617268; intellectual disability; epilepsy; regression; microcephaly

Publications

Mode of pathogenicity
Other

Teresa Zhao (Victorian Clinical Genetics Services)

Green List (high evidence)

Only missense reported to date which clustered towards the HECW domain or the C-terminal part of the protein.

Mostly de novo.
Created: 8 Sep 2020, 12:45 a.m. | Last Modified: 8 Sep 2020, 12:45 a.m.
Panel Version: 0.2976

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neurodevelopmental disorder with hypotonia, seizures, and absent language (MIM#617268)

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Genetic Health Queensland
Phenotypes
  • Neurodevelopmental disorder with hypotonia, seizures, and absent language (MIM#617268)
OMIM
617245
Clinvar variants
Variants in HECW2
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

10 Oct 2022, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: HECW2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

19 Oct 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: HECW2 were set to 27389779

19 Oct 2020, Gel status: 3

Set mode of pathogenicity

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of pathogenicity for gene: HECW2 was changed from to Other

8 Sep 2020, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: hecw2 has been classified as Green List (High Evidence).

8 Sep 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: HECW2 were changed from to Neurodevelopmental disorder with hypotonia, seizures, and absent language (MIM#617268)

8 Sep 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: HECW2 were set to

8 Sep 2020, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: HECW2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

22 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: HECW2 was added gene: HECW2 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: HECW2 was set to Unknown