Early onset or syndromic epilepsy

Gene: TET3

I don't know

Seizures reported in 2 cases with AR disease and 2 cases with AD disease. Don't think this is enough evidence to class as green.

Created: 31 Jan 2021, 9:22 p.m. | Last Modified: 31 Jan 2021, 9:22 p.m.

Panel Version: 2.281

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 31928709

Green List (high evidence)

The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Taking account the review of Helen Lord and Konstantinos Varvagiannis, there is not enough convincing evidence for this gene to be rated GREEN on the Genetic epilepsy syndromes panel. The "for-review" tag has been removed. The "watchlist" tag will remain to highlight that further cases with seizures are needed for this gene to be rated Green on this panel.

Created: 6 Aug 2020, 4:22 p.m. | Last Modified: 1 Feb 2021, 4:33 p.m.

Panel Version: 2.287

Comment on phenotypes: This recognized as TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic in Gen2Phen (https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=TET3#)T3#).

Created: 6 Aug 2020, 4:16 p.m. | Last Modified: 6 Aug 2020, 4:16 p.m.

Panel Version: 2.143

Comment on list classification: Associated with relevant phenotype OMIM and as probable Gen2Phen gene for TET3 DNA Demethylation Disorder biallelic and TET3 DNA Demethylation Disorder monoallelic. At least 9 variants reported in total, with 5 variants associated with the biallelic version of the condition in 3 unrelated cases and 4 variants associated with the monoallelic version in 4 unrelated cases. Seizures were reported in 2 unrelated cases of monoallelic and 2 unrelated cases of biallelic 2 cases TET3 DNA Demethylation Disorder.

Created: 6 Aug 2020, 4:14 p.m. | Last Modified: 6 Aug 2020, 4:14 p.m.

Panel Version: 2.141

I don't know

Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants.

For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc).

Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing.

TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC].

5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc).

6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES.

All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it.

Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization).

DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID.

Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116].
Sources: Literature

Created: 12 Jan 2020, 7:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face

Publications

• https://doi.org/10.1016/j.ajhg.2019.12.007