Intellectual disability
Gene: TNRC6B

TNRC6B (trinucleotide repeat containing 6B)
EnsemblGeneIds (GRCh38): ENSG00000100354
EnsemblGeneIds (GRCh37): ENSG00000100354
OMIM: 610740, Gene2Phenotype
TNRC6B is in 3 panels

3 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Comment on list classification: This is a borderline Amber/Green gene, and should be reviewed at the date of next GMS panel update (added 'for-review' tag).

Phenotype is primarily characterised by neurobehavioral abnormalities, including DD (particularly speech impairment) in all cases, as well as variable features of autism, ADHD, impulsivity, anger and aggressiveness. Cognitive abilities were varied, and a formal diagnosis of ID was only attained in 4 patients. Nonetheless, this likely represents the most appropriate panel for capturing these cases and therefore a Green rating should be considered.
Created: 5 Oct 2020, 11:06 a.m. | Last Modified: 5 Oct 2020, 11:06 a.m.

Panel Version: 3.375

Created: 5 Oct 2020, 11:06 a.m.
Last Modified: 5 Oct 2020, 11:06 a.m.
Panel version: 3.375

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Granadillo et al (2020 - PMID: 32152250) report on 17 unrelated individuals with heterozygous TNRC6B variants.

Features included hypotonia (10/17), DD/ID (17/17 - ID was not universal: average IQ of 12 individuals was 73 (range : 50-113) with 4 having below 70), ADHD (11/17), ASD or autistic traits (8/17 and 5/17). Some/few presented with abnormal OFC (micro- / macrocephaly in 3/17 and 2/17), abnormal vision or hearing, variable other congenital anomalies, echocardiographic, GI or renal abnormalities, etc. Epilepsy was reported in 1/17. There was no recognisable gestalt.

Variable initial genetic tests (incl. karyotype, CMA, FMR1, sequencing of other genes) were normal in most individuals with 6/17 having additional variants, in (only) 2 cases contributing to the patient's phenotype.

Detected variants were identified following exome (14/17), targeted panel sequencing (2/17) or CMA (1/17) and included 14 pLoF, 1 missense SNV and 2 intragenic deletions.

Variants had occurred as de novo events in 10/13 subjects for whom testing of both parents was possible. 3/13 subjects had inherited the variant from a parent with milder phenotype.

The protein encoded by TNRC6B (similar to TNRC6A, C) is involved in translational inhibition, through association with the Argonaute (Ago) family of proteins which are effectors of post-transcriptional gene silencing.

There were no variant studies performed.

Based on the type of variants identified, the pLI score of 1 in gnomAD and the HI index of 5.61%, the authors suggest haploinsufficiency as the most likely mechanism.

Animal models are not discussed (/possibly not available).

Individuals with de novo TNRC6B variants have also been reported in larger cohorts (e.g. DDD study - PMID: 28135719, Iossifov et al - PMID: 25363768, Lelieveld et al - PMID: 27479843, Jónsson et al - PMID: 28959963).

A previous study provided details on 2 sibs harboring a translocation which disrupted both TNRC6B and TCF20 (also associated with ID)(Babbs et al - PMID: 25228304).

Overall this gene can be upgraded to amber (ID is a feature although mild and not universal) or green rating (DD in all, >=4 subjects with ID and relevant variants). Please consider inclusion/upgrade in other relevant panels such as ASD.
Created: 6 May 2020, 3:36 p.m. | Last Modified: 6 May 2020, 3:36 p.m.

Panel Version: 3.35

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

Phenotypes
Global developmental delay; Intellectual disability; Autistic behavior

Publications

Created: 6 May 2020, 3:36 p.m.
Last Modified: 6 May 2020, 3:36 p.m.
Panel version: 3.35

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green
Victorian Clinical Genetics Services

Phenotypes

Global developmental delay
Intellectual disability
Autistic behaviour

OMIM

610740

Clinvar variants

Variants in TNRC6B

Penetrance

None

Publications

Panels with this gene