Intellectual disability syndromic and non-syndromic
Gene: HERC2

HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2)
EnsemblGeneIds (GRCh38): ENSG00000128731
EnsemblGeneIds (GRCh37): ENSG00000128731
OMIM: 605837, Gene2Phenotype
HERC2 is in 9 panels

2 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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.
Created: 13 Jul 2020, 6:07 p.m. | Last Modified: 13 Jul 2020, 6:07 p.m.

Panel Version: 0.2750

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mental retardation, autosomal recessive 38 (MIM 615516)

Publications

Created: 13 Jul 2020, 6:07 p.m.
Last Modified: 13 Jul 2020, 6:07 p.m.
Panel version: 0.2750

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

I don't know

Multiple Amish families described with same variant P594L, founder effect.
Created: 7 Feb 2020, 1:59 a.m. | Last Modified: 7 Feb 2020, 1:59 a.m.

Panel Version: 0.2024

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mental retardation, autosomal recessive 38 615516

Publications

Created: 7 Feb 2020, 1:59 a.m.
Last Modified: 7 Feb 2020, 1:59 a.m.
Panel version: 0.2024

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Genetic Health Queensland

Phenotypes

Mental retardation, autosomal recessive 38, MIM# 615516

OMIM

605837

Clinvar variants

Variants in HERC2

Penetrance

None

Publications

Panels with this gene