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Intellectual disability

Gene: HERC2

Amber List (moderate evidence)

HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2)
EnsemblGeneIds (GRCh38): ENSG00000128731
EnsemblGeneIds (GRCh37): ENSG00000128731
OMIM: 605837, Gene2Phenotype
HERC2 is in 2 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review - more than 3 distinct variants in unrelated cases presenting the relevant phenotype.
Created: 30 Jul 2020, 9:59 a.m. | Last Modified: 30 Jul 2020, 9:59 a.m.
Panel Version: 3.209

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Please consider upgrading this gene to green in the current panel based on the following updated review (13-07-2020):

Biallelic pathogenic HERC2 variants cause Mental retardation, autosomal recessive 38 (MIM 615516).

The current review is based mostly on the information provided by Elpidorou et al (2020 - PMID: 32571899) summarizing the findings in several affected individuals as published in the literature. ID was a universal feature among them (27/27) and seizures were reported in some (9/27):
- 22 subjects from Amish/Mennonite families were homozygous for p.Pro594Leu [NM_004667.5(HERC2):c.1781C>T] (Puffenberger et al 2012 - PMID: 23065719, Harlalka et al 2013 - PMID: 23243086, Abraham et al - PMID: 30902390)
- 2 additional patients were homozygous for another missense SNV [NM_004667.5(HERC2):c.4625G>A - p.Arg1542His] (Abraham et al 2019 - PMID: 30902390)
- 3 sibs born to consanguineous parents, homozygous for NM_004667.5:c.13767_13770delTGAA - p.(Asn4589LysTer4598)] as described by Elpidorou et al.
- 1 male homozygous 286 kb deletion spanning several 5' exons of HERC2 as well as the first exons of OCA2 was described by Morice-Picard et al (2016 - PMID: 27759030). Despite a neurological presentation (axial hypotonia, peripheral hypertonia, extrapyramidal symptoms and uncoordinated movements) further information was not available.

Apart from the cases summarized by Elpidorou et al, there have been few additional ones e.g. :
- Trujillano et al (2017 - PMID: 27848944) reported briefly on a patient, homozygous for NM_004667.5:c.4676-1G>A displaying seizures, hypotonia, global DD, "Encephalopathy" and abnormality of the liver.
- Yavarna et al (2015 - PMID: 26077850) provided few details with on an individual with primarily 'neurocognitive' phenotype but rather atypical presentation (MRI abnormalities, TGA, VSD, renal anomaly, growth retardation, hearing loss) due to p.Q3164X variant (recessive inheritance was specified).

Several lines of evidence support an important role for the protein encoded (an E3 ubiquitin protein ligase, interacting also with UBE3A, involved in several cellular processes incl. cell cycle regulation, spindle formation during mitosis, mitochondrial functions, DNA damage responses by targeting proteins such as XPA) as well as the effect of the reported variants (mRNA studies, Western blot, detection of a fusion transcript in the case of the deletion, etc).

Individuals from the Amish families displayed Angelman-like features (in line with HERC2-UBE3A interaction) with - among others - gait instability. Mouse models recapitulate some of these features (e.g. the movement disorder) as extensively discussed by Abraham et al.

Overall this gene can be included in the ID and epilepsy panels with green rating.

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Created: 13 Jul 2020, 6:13 p.m. | Last Modified: 13 Jul 2020, 6:13 p.m.
Panel Version: 3.170
PMID 23065719 describes 7 affected individuals from 3 sibships (from the Amish or Mennonite populations) homozygous for a missense variant (c.1781C>T/p.Pro594Leu). All individuals presented with DD/ID, autistic behavior and gait instability. Functional studies demonstrated decreased HERC2 abundance.

In PMID 23243086, 15 subjects from 2 large Amish families are reported, with similar phenotype including hypotonia, DD/ID, unstable gait with broad base and arms held upward and seizures in a few individuals. All the patients were homozygous for the same missense variant reported in 23065719. Levels of HERC2 were shown to be diminished in fibroblasts from affected individuals.

Given some phenotypic similarities with AS, both studies excluded methylation abnormalities at the SNRPN locus (as well as UBE3A pathogenic variants in 23065719).
Created: 12 Aug 2018, 8:51 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mental retardation, autosomal recessive 38, 615516

Publications

Zornitza Stark (Australian Genomics)

I don't know

Three sibships with bi-allelic variants reported in this gene; however likely founder effect. Suggest inclusion as Amber or Red.
Created: 22 Jun 2018, 11:19 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mental retardation, autosomal recessive 38

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Mental retardation, autosomal recessive 38
Tags
for-review
OMIM
605837
Clinvar variants
Variants in HERC2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

30 Jul 2020, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: HERC2.

30 Jul 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: herc2 has been classified as Amber List (Moderate Evidence).

28 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to HERC2.

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

HERC2 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

HERC2 was created by Zornitza Stark